Journal of Clinical Oncology (JCO) Podcast

The Journal of Clinical Oncology Podcast presents analyses and discussions centered on the latest findings published in ASCO’s flagship Journal of Clinical Oncology. Host Dr. Davide Soldato facilitates interviews and scholarly discourse on the most impactful published findings. The Journal of Clinical Oncology Podcast is the trusted resource that empowers you to integrate cutting-edge evidence into clinical practice. The year’s fellows interview authors and summarize the top Journal of Clinical Oncology articles in the series, JCO Article Insights.

Adjuvant Durvalumab and the Future of Early-Stage NSCLC 05/14/2026

JCO Article Insights: LEAP-010 Study in Recurrent/Metastatic Head and Neck Cancer 04/27/2026

Infections in Two Diet Strategies in HSCT and Leukemia Patients 04/09/2026

JCO Article Insights: ctDNA in DLBCL - Ready for Prime Time? 03/30/2026

JCO Article Insights: ctDNA in DLBCL - Ready for Prime Time? In this episode of JCO Article Insights, host Dr. Ash Gurumurthi summarizes JCO articles, "" and " " TRANSCRIPT Ash Gurumurthi: Hi and welcome to . I'm your host, Ash Gurumurthi, and today we will be discussing two articles, both published in the , on the real-world utility of circulating tumor DNA (ctDNA) MRD in newly diagnosed large B-cell lymphoma. The first study is the article "" by Dr. Joanna Krupka and colleagues in the United Kingdom. For the sake of convenience, I'll refer to this as the DIRECT study. The second study is "" by Dr. Steven Wang and colleagues in the Netherlands, referred to as the HOVON 902 study. By way of background, I wanted to talk about MRD in hematolymphoid malignancies. Nodal diseases have lacked a robust biomarker for end-of-treatment response. They have relied historically on PET scans interpreted using the semiquantitative Deauville 5-point scale, which has a high negative predictive value but a limited positive predictive value. The poor positive predictive value for survival results in extended follow-up with serial imaging for risk stratification with unnecessary and invasive biopsies. There have been recent revolutionary advancements in ctDNA MRD in B-cell lymphoma. The use of ctDNA in lymphoma began with CAPP-seq, which tracked single nucleotide variants that were tumor specific but was limited by excessive background sequencing noise with false negatives. To overcome this, Dr. Kurtz and colleagues developed the proprietary PhasED-seq assay. This tracks well-recognized phased mutations on the same DNA strand in cis configuration within hypermutated regions that are unique to B-cell lymphoma. Using this method, they pushed their limit of detection at 95%, the so-called LOD95, to 0.7 parts per million under optimal circumstances with 120 nanograms of input cell-free DNA from plasma. Based on the use of the PhasED-seq assay in trials of newly diagnosed large B-cell lymphoma with the use of investigational agents, the NCCN currently recommends consideration of ctDNA MRD assay with a detection limit of less than 1 part per million if biopsy is not feasible for a positive end-of-treatment PET. However, I believe this threshold needs reconsideration given it is based on an ideal assay LOD95 under optimal circumstances rather than sample-specific LOD95. Real-world validation of the role of end-of-treatment ctDNA and appropriate thresholds for sample-specific LOD95 were lacking until the publication of these two studies. The DIRECT and the HOVON 902 studies were multicenter, prospective trials using real-world cohorts of newly diagnosed large B-cell lymphoma treated with standard anthracycline immunochemotherapy, ie, R-CHOP chemotherapy. They validated end-of-treatment ctDNA MRD response measured on a phased-variant platform and found them to be strongly prognostic for relapse and survival. This was independent of PET imaging or baseline clinical prognostication like the International Prognostication Index, the IPI. They also demonstrated a threshold with an LOD95 of approximately 1 in 100,000 is necessary for clinical utility. Both trials recruited over a similar period between 2020 to 2023, with the DIRECT study conducted within the National Health Service in the United Kingdom and the HOVON 902 as a national study in the Netherlands. For survival analysis, only patients who reached the landmark event of end of treatment with an available ctDNA MRD sample without progressive disease or death at that time point were included. These studies evaluated similar-sized cohorts with 134 patients for HOVON 902 and 151 patients for the DIRECT study. As expected, their baseline demographics are reflective of a real-world population of newly diagnosed cases with large B-cell lymphoma. Although both used comparable statistical methodologies with time-to-event analysis, the primary outcomes vary, making headline comparisons quite challenging. The DIRECT study utilized the time to tumor progression, censoring death unrelated to disease. This was done to isolate the molecular impact of detectable ctDNA at the end of treatment. In contrast, the HOVON 902 study used progression-free survival, which counts all-cause mortality as an event. This naturally results in lower event-free rates for PFS compared to TTP in the DIRECT study. The trials differed in their choice of phased-variant platforms, with the DIRECT study developing an independent, fully open-source phased-variant ctDNA assay. This has been released on GitHub. In contrast, the HOVON 902 study utilized PhasED-seq by Foresight Diagnostics, which is currently the only proprietary and commercially available phased-variant assay for lymphoid malignancies. Interestingly, despite the differences in platforms and the primary end points, the results were remarkably consistent. The DIRECT study found a highly significant difference in the 2-year TTP rate of 96% in those with undetectable ctDNA MRD at the end of treatment compared to 45% in those with detectable ctDNA, with a hazard ratio of 15. Similarly, the HOVON 902 study found a significantly superior 3-year PFS of 85% in those with undetectable ctDNA compared to 17% with detectable ctDNA, with a hazard ratio of 10. Crucially, both studies found end-of-treatment ctDNA MRD significantly outperformed PET response assessment for long-term PFS. In fact, for the end point of PFS in both trials, the baseline IPI lost all statistical significance in both univariate and multivariable analysis when accounting for ctDNA MRD and PET status at the end of treatment. While both studies demonstrate the superiority of ctDNA MRD compared to PET in predicting survival, interestingly, the combination of both tests appeared to be complementary in identifying the highest-risk group. The HOVON 902 study identified 13 patients who were double positive, ie, they were positive with end-of-treatment PET and detectable ctDNA MRD. Every single one of these patients progressed over a 3-year period with a dismal overall survival of 17%. The DIRECT study mirrored these findings with the same double-positive group having a 2-year time to progression rate of 23%. Given consistency in identifying the poor outcome of this double-positive population in both studies, this is clearly a group that would benefit from trial-based approaches like consolidation or, alternatively, frequent surveillance for clinical relapse. On the other hand, the best-performing group was the double negative, ie, those who had achieved PET negative and ctDNA undetectable at the end of treatment. The double-negative group had a 2-year time to progression of 97% in the DIRECT study and a 3-year PFS of 88% in the HOVON 902 trial. This is quite impressive. Based on these findings, we can anticipate that ctDNA may complement rather than wholly replace PET at the end of treatment for response assessment. Perhaps the most critical finding from both studies challenged current NCCN-recommended ctDNA MRD sensitivity threshold of achieving less than one part per million. While phased-variant assays can theoretically detect this, this is under optimal conditions, specifically 120 nanograms of input cell-free DNA. In both trials, only 3% of samples could achieve this sensitivity, with the vast majority limited to a sample-specific LOD95 of approximately 1 in 100,000 informative reads. The primary constraint was simply limited plasma volume collected, a denominator problem of input cell-free DNA. For example, the HOVON 902 study had a median plasma volume of 5 mL, yielding 20 nanograms of input DNA. The DIRECT study elegantly demonstrated bridging the gap to attain the NCCN standard of LOD95 of less than 1 part per million is practically impossible. This would require greater input DNA, attained through a 20- to 30-milliliter collection of plasma rather than the standard 10 milliliters, and a massive 20- to 40-fold increase in sequencing depth. With the current real-world sensitivity of roughly 1 in 100,000 in both these studies, the negative predictive value is already nearly at 90%. There is going to be diminishing returns for further analytical sensitivity. This strongly suggests that the NCCN guidelines should be updated to prioritize achievable sample-specific LOD95 rather than assay-specific theoretical limits. Collectively, these studies validate the real-world utility of ctDNA MRD as an independent predictor of long-term outcomes following first-line therapy of large B-cell lymphoma. Finally, after two decades of the default R-CHOP for all, the field of aggressive large B-cell lymphoma is taking leaps and bounds by integrating ctDNA MRD with the current wave of bispecific and cellular therapies. I want to now leave you with my five key clinical takeaways from both these studies. ● Firstly, ctDNA MRD is a more potent independent predictor of outcome than end-of-treatment PET/CT and baseline IPI. ● Second, ctDNA MRD in first-line large B-cell lymphoma is already reshaping clinical trial space with therapeutic escalation and de-escalation strategies based on ctDNA kinetics during treatment, as well as identifying candidates with persistent ctDNA at the end of treatment for consolidation approaches. ● Thirdly, this technology is ready for prime time. Whether this is through Foresight's PhasED-seq assays or the open-source method released by the DIRECT group, academic centers can now operationalize this in routine clinical care. ● Fourth, biology clearly provides a ceiling. Current sensitivity goals of less than one part per million as recommended by the NCCN are limited by the actual amount of cell-free DNA we can extract from a patient's blood, not just the assay's technology. I believe these two studies will inform the NCCN's next revision to move away from theoretical assay limits to a more realistic sample-specific LOD95 of approximately 1 in 100,000. ● Finally, it appears that the end-of-treatment ctDNA MRD test may be complementary to PET/CT rather than a replacement. Clearly, the best outcomes are seen in double-negative patients, while double-positive results, ie, positive end-of-treatment PET and detectable ctDNA at the end of treatment, identify a group with an extremely high risk of early progression who may need early intervention. Thank you for listening to . Please come back for more interviews and article summaries, and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit . The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. /episode/index/show/jcopodcast/id/40643860

The CISTO Study: Radical Cystectomy or Bladder-Sparing Therapy for Recurrent NMIBC 03/12/2026

The CISTO Study: Radical Cystectomy or Bladder-Sparing Therapy for Recurrent NMIBC Guest Dr. John Gore and host Dr. Davide Soldato discuss JCO article, "," which compares radical cystectomy and bladder sparing therapy for patients with recurrent high-grade non-muscle invasive bladder cancer. Dr. Gore and Dr. Soldato focus on the study's patient-centered approach, eligibility criteria, and quality of life after treatment. TRANSCRIPT The disclosures for guests on this podcast can be found in the show notes. Dr. Davide Soldato: Hello and welcome to , the podcast where we sit down with authors from some of the latest articles published in the . I am your host, Dr. Davide Soldato, medical oncologist at Ospedale San Martino in Genoa, Italy. Today, we are joined by author Dr. John Gore, urologist at Fred Hutch Cancer Center and professor of urology at University of Washington School of Medicine. Today, we will be discussing the article titled, "." Thank you for speaking with us, Dr. Gore. Dr. John Gore: Thank you so much for having me. Dr. Davide Soldato: So, I just want to jump right in. We know that patients who are diagnosed with recurrent high-grade non-muscle-invasive bladder cancer can be treated with two different approaches. So, one is radical cystectomy, and the other is bladder-sparing therapy. I just wanted to understand: what was the gap that you were trying to fill with this study? In particular, one point that is very important is that this study is very centered on the preference of the patients. Why did you choose this endpoint instead of going for more solid oncology-based endpoints? Dr. John Gore: Yeah, so CISTO was a study that was derived really organically from patient engagement. I think as a clinical gap in care, making a decision about when to pursue radical cystectomy for patients with non-muscle-invasive bladder cancer is a tough decision for us as clinicians. We did some engagement work partnered with the Bladder Cancer Advocacy Network and my partner Angela Smith, and found that it is also a huge gap for patients. You know, they are very anxious about recurrences, and the decision about when to take out the bladder is a very difficult one. We did an evidence synthesis and found that evidence guiding this decision is fairly limited. The reason we chose more of a patient-reported endpoint is several-fold. One is that we, as part of our engagement work, also worked with our patient survey network to identify outcomes that were important to patients. Some of those are the same outcomes that we care about as clinicians - recurrence-free survival and metastasis-free survival - but several outcomes came out that were more patient-centered. These were patient-reported outcomes such as the burden on my finances, the burden on my caregiver or loved one, and the ability to return to physical activities that are important to them. Part of what is unique about CISTO is that this was a contract with PCORI where we knew we would only have about 12-month outcomes for the majority of our patients. That is too early to really derive a lot of the clinical outcomes, but we are able to answer that patient-centered question of, "Am I going to be able to return to physical activities that are important to me?" And that was the genesis of that as the primary endpoint. Dr. Davide Soldato: So, who were the patients that were eligible to participate in the CISTO trial? What were the key eligibility criteria? This is very particular to this study because this was actually an observational study. Why did you think that such a pragmatic approach still can inform us on what is the best treatment approach for these patients? Dr. John Gore: The intent of CISTO was not necessarily to focus on the tightly defined BCG-unresponsive patient population. That is a clearly important patient population, but every day we are all faced in our real-world practice with patients with challenging, high-grade recurrences that don't fit neatly into that BCG-unresponsive box. The reason we chose a broader inclusion was to help doctors and patients answer these same questions they have when it doesn't fit nicely into this BCG-unresponsive category. You know, maybe their BCG exposure was two years ago, but now they are having a recurrence after intravesical chemotherapy. That is no less challenging a clinical conundrum, and we wanted to be able to enroll those patients. Other key inclusions were that all of the patients in CISTO had to have BCG at some point, and they had to have recent exposure to some adjuvant instillational or intravenous therapy like pembrolizumab. We also had some exclusions that were important. They couldn't be participating in a phase 2 clinical trial, and they couldn't have had a prior upper tract urothelial cancer. The other point about the observational trial design is I think a really important one. Part of our engagement work also asked patients about their willingness to randomize. There is a ton of literature in our history of trials that failed to accrue well when they were comparing a large-scale surgical intervention with a more conservative management strategy. What we found is only about 10% of patients would be willing to randomize when the clinical comparison is between radical cystectomy and bladder-sparing therapy. So it was very clear that an observational study design was the only way we were going to get evidence to inform clinical care when one of the key comparators was radical cystectomy. And so that is why we utilized the observational trial design. Dr. Davide Soldato: Starting to go deeper into the results, you mentioned before that the endpoint you chose for this trial was really centered on what patients thought was more important to them. In particular, the primary endpoint of the study was physical function as measured by the EORTC QLQ-C30 questionnaire. I just wanted to understand: first, did you have a solid hypothesis regarding how physical function could be impacted by either radical cystectomy or bladder-sparing treatments? And second, what were the key results of the study? Dr. John Gore: We figured that at 12 months after enrollment, given the burden and morbidity of a radical cystectomy, that patients in the radical cystectomy arm would have worse self-reported physical functioning than patients in the bladder-sparing therapy arm. We did hypothesize that some of our secondary outcomes might potentially be better after radical cystectomy, such as recurrence-free survival and potentially some other cancer-specific outcomes, because it is a more definitive management strategy. For our primary endpoint, however, we hypothesized that it would be worse. What we found, and the key finding of our study, is that at 12 months after enrollment, physical functioning was not different between patients undergoing radical cystectomy and patients undergoing bladder-sparing therapy, which is just important in terms of clinical counseling because it just means that you can tell your patients, "Gosh, if we could fast-forward your life six to nine months after this procedure, your physical functioning would be similar to as if you had been able to keep your bladder." Dr. Davide Soldato: And you mentioned that there were some key secondary endpoints of the study, which included both other dimensions of quality of life and also hard clinical outcomes. We mentioned metastasis-free survival, for example. Going a little bit into the key secondary quality of life outcomes, we know that radical cystectomy can impact physical functioning, but we also know that bowel, sexual symptoms, and also genitourinary symptoms might potentially be impacted by this type of treatment. We also know that, especially in a system like the US, financial toxicity can be a significant burden for patients. Considering the two different approaches, was radical cystectomy better also in other key secondary quality of life outcomes, and was financial toxicity different between the two arms? Dr. John Gore: Thank you for highlighting some of the really important secondary outcomes that I think are really important to trying to figure out what's best for your patients. Some of the main ones were some of the bladder cancer-specific quality of life outcomes you highlight. Urinary quality of life was worse at enrollment in patients in the radical cystectomy arm but was no different 12 months after. What is unique about how we measure that is we used an instrument called the Bladder Cancer Index because we're comparing a population of patients who have lost their bladder with a population of patients who have retained their bladder, and there are different considerations by gender. And so that instrument is agnostic to urinary diversion status and gender. We found that bowel function and sexual function were worse in the radical cystectomy arm. It appeared that bowel functioning was getting better to the point of near equivalence at 12 months in the radical cystectomy arm but was still inferior to bladder-sparing therapy, and that probably relates to the fact that we use the bowel as part of the urinary diversion, and that causes some transient disruption in bowel function. Financial toxicity is an outcome we weren't initially planning on having as part of the CISTO study, but based on that patient feedback, we made that one of our key secondary outcomes. That actually demonstrated superiority in the radical cystectomy arm. I think it's important that we remember that when we do bladder-sparing therapy, those patients are predisposed to a number of visits to our office, whether they're for instillational therapies or cystoscopy surveillance visits. Sometimes that involves the patient themselves, and sometimes that involves a caregiver. We live in an area with a very large geographic catchment, so sometimes that involves overnight hotel stays and airfare. It can be a particular burden, as you made mention, especially in our healthcare system. Dr. Davide Soldato: Going back to the quality of life dimensions and especially considering the different treatments, 50% of the patients received radical cystectomy with robotic surgery. Did you look a little bit into whether the type of surgery that they received might potentially impact on these dimensions of quality of life? Dr. John Gore: These are some questions that a lot of urologists have asked us in the surgical arm, related to surgical approach, so robotic versus open, and urinary diversion type. We sometimes reconstruct the urinary tract with an incontinent diversion called an ileal conduit where the urine drains tonically into a bag, and we sometimes do a continent diversion where someone typically will have a neobladder, where you reconstruct a sphere reservoir out of intestines and sew it to the urethra. About 20% of patients in the radical cystectomy arm in CISTO had a neobladder. We have not yet looked at specific surgical factors and some of those outcomes. That is one of the secondary analyses that we have planned, but we have not drilled into how different surgical approach factors can affect some of our outcomes. Fortunately, we have about 200 patients in the radical cystectomy arm, so it's enough patients that hopefully we can look at some of those factors in the future. Dr. Davide Soldato: Going back to the clinical endpoints, you mentioned that several of these were measured. There was metastasis-free survival, cancer-specific survival, and progression-free survival. We now have the data at 12 months. I am just wondering if you can comment on those when comparing the radical cystectomy with the bladder-sparing techniques. Dr. John Gore: I think importantly, bladder cancer-specific survival was very high in both arms, over 95% at one year. So both patient populations do very well in terms of cancer-specific and overall survival at one year. You know, when you take out the bladder, you're taking out a big source of recurrences. Not surprisingly, there was a marked reduction in recurrences in the radical cystectomy arm, so they had better recurrence-free survival. There actually was worse progression-free survival in the radical cystectomy arm, but there is a big asterisk to that. As you noted, it is an observational study, and one of the areas of imbalance in the study is that we had higher cancer severity in the radical cystectomy arm. So there was about a 20% rate of progression at the time of radical cystectomy to muscle-invasive and node-positive disease. Of those progressions, the overwhelming majority of them were progressions at the time of radical cystectomy, which I think speaks to a couple of important factors. Number one is the challenge in staging these patients. Our staging of non-muscle-invasive bladder cancer is very reliant on our resection. And so there is this risk of understaging our patients. Number two is just the challenge of decision making, that we fear losing our window of cure in this patient population, which is why we try to steer some patients toward radical cystectomy, and that progression figure kind of speaks to that. Dr. Davide Soldato: Also, one of the factors that was most common in the patients who received radical cystectomy was the presence of other high-risk features. For example, non-urothelial histology, which I think is something that in clinical practice we tend to fear a little bit in terms of recurrence, and so it might potentially bias a little bit towards proposing more strongly radical cystectomy to the patient. Another thing that I wanted to have a comment on, so this is not really in the paper, but I think it speaks a little bit to how the data will evolve over time. Do you imagine these clinical outcomes changing over time, and do you think that with higher maturity of these endpoints, this study might be even more informative when counseling patients regarding what they are obtaining with a radical cystectomy versus the other type of treatments? Dr. John Gore: You know, I think in this cancer universe, 12-month outcomes are great, but I think we all want to see two-year and five-year outcomes. We're very fortunate to supplement the work that we've done in the initial CISTO study, we’re very fortunate that we've gotten supplementary funding from the National Cancer Institute to get long-term outcomes in this patient population. So we are continuing to follow all of our CISTO study patients to get two-year and five-year outcomes. What we expect to find is the accrual of new events in the bladder-sparing therapy arm. About 7% of patients in the bladder-sparing therapy arm underwent cystectomy in the first year, but that number will probably go up either as they have recurrences or progression events. We definitely expect the recurrence-free survival to continue to have superiority in the cystectomy arm, but we probably will see the progression events equilibrate as more progression events accrue in the bladder-sparing therapy arm. Maybe by five years, we hypothesize that we'll see clinical superiority in the radical cystectomy arm. By then, we might also see mortality events that separate bladder cancer-specific survival and overall survival between the two arms potentially. But we don't know. Hypothetically, cystectomy has its own downstream risks. It is a major reconstruction with some metabolic sequelae and renal functional sequelae, and so there may be some general medical events that accrue in the cystectomy arm that are also impactful. Dr. Davide Soldato: One other thing that I think should be complimented on this study is that you also looked at several other endpoints that might be important for patients. For example, anxiety symptoms and depression symptoms. Dr. John Gore: Yeah, I think one of the other key secondary outcomes we looked at were mental health outcomes. We utilized the PROMIS domains of anxiety and depression. Not unexpectedly, our radical cystectomy arm patients exhibited higher anxiety symptoms and higher depression symptoms at enrollment. What we found is at 12 months, they actually had significantly lower anxiety and depression than patients in the bladder-sparing therapy arm. We hypothesized in this paper that that actually relates probably mostly to cancer-specific anxiety. You know, when you experience this cavalcade of recurrences, it just breeds an anxiety about adverse cancer-specific outcomes, and by taking out the bladder, you kind of eliminate this prevalent source of anxiety. We followed up the study with a qualitative piece where we interviewed 50 patients and 20 caregivers. Based on those interviews, and that's just a sample of the patient population, it did seem to be cancer-specific anxiety that was driving a lot of those responses. Dr. Davide Soldato: I would like to end with a methodological consideration on your part because we said that this was an observational study. Frequently we tend to think that observational studies come with a lot of bias, and so we tend to downgrade a little bit the results. But I think that a lot of the merit that goes in the CISTO study that was published in the JCO, and I think it also speaks to the fact that this is very high-quality data, comes with the fact that the methodology behind this study was really robust in terms of informing us. Even with this observational study that, as you said, was the only one that we could perform considering the patient population. So just a comment on your part also to speak to the solidity of the data that was published. Dr. John Gore: Importantly, you know, if you look at or other sources, CISTO is the only trial that has radical cystectomy as a major comparator. In many ways, this study is our only source of evidence for radical cystectomy. So we'd rather have flawed observational evidence than no evidence at all. We all experience flaws of our RCTs as well. They tend to be these narrowly defined patient populations that may not match the patient in front of you. So I think there are unrecognized flaws on the other side as well. The way that we try to counterbalance that, and none of these techniques are perfect, but we used a strategy called ‘targeted maximum likelihood estimation’. Like many methods, such as propensity scores or instrumental variable analysis, what we're trying to do theoretically is coax randomization from non-randomized data. And TMLE, which is the technique we use, tends to be pretty robust to that. So it's the best available way that we can try to counterbalance the bias based on age and clinical severity between the two patient arms. I also think what's important about this is that even when there are biases, I think we are able to infer those out and still extract meaningful details from the data. So even with the biased data, I think we all glean some really important clinical learnings from it. Dr. Davide Soldato: Absolutely, but I would also say that in terms of observational data, the work that you have done is really something that makes us quite confident about what you found in the CISTO study. So with this, I would like to thank you again for joining us today. Dr. John Gore: Thank you so much, and thank you for highlighting the CISTO study. We are very excited about the data. Dr. Davide Soldato: So Dr. Gore, we appreciate you sharing more on your JCO article titled, ." If you enjoy our show, please leave us a rating and review and be sure to come back for another episode. You can find all ASCO shows at The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Guest Disclosure Dr. Gore:Consulting or Advisory Role: Astellas... /episode/index/show/jcopodcast/id/40402095

JCO Article Insights: Atezolizumab, Bevacizumab, and Non-Platinum Chemotherapy for PROC 02/23/2026

JCO Article Insights: Atezolizumab, Bevacizumab, and Non-Platinum Chemotherapy for PROC In this episode of JCO Article Insights, host Dr. Melis Canturk summarizes the article, “” by Harter et al. TRANSCRIPT Melis Canturk: Hello, and welcome to the . I'm your host, Melis Canturk, and today we will be discussing the article, “.” While integrating immune checkpoint inhibitors has revolutionized the treatment of various gynecologic cancers, these agents have historically shown limited single agent activity in ovarian cancer. Despite a strong biological rationale for combining immunotherapy with chemotherapy and bevacizumab to enhance T-cell infiltration and normalized tumor vasculature, several phase III trials have failed to demonstrate a significant survival benefit in this setting. The AGO-OVAR 2.29/ENGOT-ov34 trial was launched to definitely evaluate whether adding the PD-L1 inhibitor atezolizumab to this combination could improve long-term outcomes for patients experiencing early relapse. This international, double-blind, randomized phase III trial enrolled 574 patients with epithelial ovarian, fallopian tube, or peritoneal cancer. Eligible participants had to be in their first or second relapse within 6 months of completing platinum therapy or in their third relapse regardless of the treatment-free interval. All patients received bevacizumab and an investigator selected chemotherapy backbone, either paclitaxel or doxorubicin. They were randomly assigned to receive either 840 mg of atezolizumab or a placebo every 2 weeks until disease progression or for a maximum of 2 years. The study population was an all-comer group, though patients were stratified by their PD-L1 status, previous bevacizumab use, and the number of prior treatment lines. The trial did not meet its primary end points, as the addition of atezolizumab failed to significantly improve overall survival or progression-free survival in the intention-to-treat population. For the primary end point of overall survival, the median was 14.2 months with atezolizumab compared to 13 months with the placebo. Progression-free survival was similarly insignificant, with a median of 6.4 months in the experimental arm versus 6.7 months in the control arm. Furthermore, the objective response rates were nearly identical between the groups, recorded at 40% for atezolizumab and 44% for the placebo. Interestingly, exploratory subgroup analyses revealed potential signals of benefit in specific populations, even though the overall trial was negative. Patients who had been previously treated with bevacizumab appeared to derive a greater benefit from the addition of atezolizumab than those who were bevacizumab-naïve. Additionally, outcomes seemed more favorable for patients receiving a paclitaxel chemotherapy backbone compared to those receiving doxorubicin. However, PD-L1 status did not appear to be a predictive marker for success, as hazard ratios for survival were similar regardless of whether the tumor was PD-L1 positive or negative. The safety profile of the triple combination was consistent with the known toxicities of the individual drugs. Grade 3 or higher adverse events occurred in 73% of the atezolizumab group and 70% of the placebo group. While the experimental arm saw higher incidences of immune-mediated events, such as thyroid-related issues, these were generally manageable. Serious adverse events were more frequent in the atezolizumab arm than in the placebo arm, but discontinuation rates due to toxicity were relatively low and comparable between the two groups. In conclusion, the AGO-OVAR 2.29 trial confirms that adding atezolizumab to bevacizumab and nonplatinum chemotherapy does not provide a statistically significant survival advantage for patients who receive nonplatinum chemotherapy for recurrent ovarian cancer. This study contributes to the growing body of evidence showing that immune checkpoint inhibitors have yet to find a definitive role in the standard treatment of recurrent ovarian cancer. Future research will likely focus on more sophisticated molecular stratification and the use of novel agents, such as bispecific antibodies, to overcome the challenging tumor microenvironment of low-grade serous ovarian cancer. Thank you for tuning into . Don't forget to subscribe and join us next time as we explore more groundbreaking research shaping the future of oncology. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. /episode/index/show/jcopodcast/id/40179505

JCO Article Insights: Ribociclib Plus Letrozole in Recurrent LGSOC: GOG 3026 02/23/2026

JCO Article Insights: Ribociclib Plus Letrozole in Recurrent LGSOC: GOG 3026 In this episode of JCO Article Insights, host Dr. Melis Canturk summarizes the article, "" by Slomovitz et al. TRANSCRIPT Melis Canturk: Hello, and welcome to . I'm your host, Melis Canturk, and today we will be discussing the article, "." Building on the fact that more than 95% of low-grade serous carcinoma are estrogen receptor positive and often exhibit abnormalities in the CDK4/6 signaling pathway, researchers launched the GOG 3026 trial. This study investigated the effectiveness of pairing the CDK4/6 inhibitor ribociclib with letrozole, an aromatase inhibitor, adapting a therapeutic approach that has already transformed the treatment landscape for hormone receptor-positive metastatic breast cancer. Low-grade serous ovarian cancer is a rare malignancy characterized by its hormonally driven nature and relative resistance to traditional platinum-based chemotherapy. While it's associated with longer survival than high-grade serous carcinoma, recurrent disease presents a significant clinical challenge due to low response rates to standard treatments. The GOG 3026 trial was an open-label, single-arm, multicenter, phase 2 study that enrolled 51 women with measurable, recurrent, low-grade serous ovarian cancer. To ensure diagnostic accuracy, all cases underwent central pathology review. Participants were required to be at least 18 years old with an ECOG performance status of 0 to 2. While there was no limit on the number of prior therapies, patients were excluded if they had previously used CDK4/6 inhibitors. Prior endocrine therapy was permitted only if the patient had discontinued it at least 6 months before the study and had not experienced disease progression while on that specific therapy. Additionally, women with intact ovarian function were required to undergo ovarian suppression. The treatment regimen consisted of 600 mg of oral ribociclib daily for the first 21 days of a 28-day cycle, paired with a continuous daily dose of 2.5 mg of letrozole. The trial's primary endpoint was the investigator-assessed objective response rate. The results were clinically meaningful. The confirmed overall response rate was 30.6%, which included one complete response and 14 partial responses. The clinical benefit rate, which includes stable disease, reached 84%. These outcomes are particularly notable given the heavily pretreated study population, where nearly 40% of patients had received three or more prior lines of systemic therapy. Durability and survival data further underscored the potential of this combination. Among those who responded to treatment, the median duration of response was 21.2 months. The median progression-free survival was 14.5 months, and the median overall survival reached 44.5 months. In terms of safety, the profile was consistent with previous CDK4/6 inhibitor studies. The most common grade 3 and 4 adverse event was neutropenia, occurring in 47% of patients. However, it was asymptomatic and managed through dose modification. Only 4% of patients discontinued the trial due to adverse events, and no dose-limiting toxicities were observed. When comparing these results to other therapeutic benchmarks, the ribociclib-letrozole combination demonstrated more favorable outcomes than historical endocrine monotherapy. It yields response rates of only 13% to 14%. Furthermore, while MEK inhibitors like trametinib or the combination of avutometinib defactinib show similar response rates, the ribociclib-letrozole regimen displayed significantly better tolerability. Specifically, only 4% of patients in this trial discontinued the therapy due to adverse events, compared to much higher discontinuation rates seen with MEK inhibitor strategies. In conclusion, the GOG 3026 trial successfully establishes ribociclib plus letrozole as a clinically active and well-tolerated regimen for recurrent low-grade serous ovarian cancer. By achieving durable disease control in a heavily pretreated, relatively chemoresistant population, this combination may redefine the therapeutic paradigm for this rare cancer. These findings support the continued evaluation of CDK4/6 endocrine strategies as a preferred chemotherapy-sparing option that prioritizes both disease control and patients' quality of life. Thank you for tuning into . Don't forget to subscribe and join us next time as we explore more groundbreaking research shaping the future of oncology. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. /episode/index/show/jcopodcast/id/40179400

NCI Working Group on Biochemically Recurrent Prostate Cancer 02/12/2026

NCI Working Group on Biochemically Recurrent Prostate Cancer Host Dr. Davide Soldato and guests Dr. David Einstein and Dr. Ravi Madan discuss JCO article, "," underscoring the need for a consensus on clinical trial designs implementing novel endpoints in this population and the importance of PSA doubling time as a prognostic factor, with an emphasis on treatment de-escalation to limit toxicity and improve patient outcomes. TRANSCRIPT The disclosures for guests on this podcast can be found in the show notes. Davide Soldato: Hello and welcome to , the podcast where we sit down with authors from some of the latest articles published in the . I am your host, Dr. Davide Soldato, medical oncologist at Ospedale San Martino in Genoa, Italy. Today, we are joined by authors Dr. David Einstein and Dr. Ravi Madan. Dr. Einstein is a medical oncologist specializing in genitourinary malignancy working at Beth Israel Deaconess Medical Center, part of the DFCI Cancer Center, and an assistant professor at Harvard Medical School. Dr. Madan is a senior clinician at the National Cancer Institute (NCI), where he focuses on conducting clinical research in prostate cancer, particularly in the field of immunotherapy. Today, we will be discussing the article titled, "." So, thank you for speaking with us, Dr. Einstein and Dr. Madan. David Einstein: Thanks for having us. This is a great pleasure. Ravi Madan: Appreciate being here. Davide Soldato: So, I just want to start from a very wide angle. And the main question is why did you feel that there was the need to convey a consensus and a working group to talk about this specific topic: biochemically recurrent prostate cancer? What has been the change in current clinical practice and in the trial design that we are seeing nowadays? And so, why was it necessary to convey such a consensus and provide considerations on novel clinical trials? David Einstein: Yeah, so I think it's very interesting, this disease state of biochemically recurrent prostate cancer. It's very different from other disease states in prostate cancer, and we felt that there was a real need to define those differences in clinical trials. Years ago, metastatic castration-resistant prostate cancer was the primary disease state that was explored, and over time, a lot of things shifted earlier to metastatic disease defined on a CAT scan and bone scan to an earlier disease state of metastatic castration-sensitive prostate cancer. And the clinical trial principles from late-stage could be applied to MCSPC as well. However, BCR is very different because the patients are very different. And for those reasons, there are unique considerations, especially in terms of toxicity and treatment intensity, that should be applied to biochemically recurrent prostate cancer as opposed to just using the principles that are used in other disease states. And for that reason, we thought it was very important to delineate some of these considerations in this paper with a group of experts. Davide Soldato: Thanks so much. So, one of the main changes that have been applied in recent years in clinical practice when looking at biochemically recurrent prostate cancer is the use of molecular imaging and particularly of PSMA PET. So, first of all, just a quick question: was the topic of the consensus related on which threshold of PSA to use to order a PET scan to evaluate this kind of patient? David Einstein: Yeah, thanks for that question. It's a super important one. The brief answer is that no, we did not address questions about exactly when clinicians would decide to order scans. We were more concerned with the results of those scans in how you define different disease states. But I think as a broader question, I think a lot of folks feel that finding things on a scan equates that with what we used to find on conventional scans. And fundamentally, we actually sought to redefine that disease space as something that's not equivalent to metastatic disease, and rather coined the term "PSMA-positive BCR" to indicate that traditional BCR prognostic criteria and factors still apply, and that these patients have a distinct natural history from those with more advanced metastatic disease. Ravi Madan: And if I may just add that the National Cancer Institute is running a trial where we're prospectively monitoring PSMA-positive BCR patients. And that data is clearly showing that, much like what we knew about BCR a decade ago, PSMA findings in BCR patients do not change the fact that overall, BCR is an indolent disease state. And the findings, which are usually comprised of five- to seven-millimeter lymph nodes, do not endanger patients or require immediate therapy. And so, while PSMA is a tool that we can be using in this disease state, it doesn't really change the principal approach to how we should manage these patients. And as Dr. Einstein alluded to, there is a drive to create a false equivalency between PSMA-positive BCR and metastatic castration-sensitive prostate cancer, but that is not supported by the data we're accumulating or any of the clinical data as it exists. Davide Soldato: One thing that it's very important and you mentioned in your answer to my question was actually the role of PET scan and conventional imaging, so CAT scan and bone scan that we have used for years to stage patients with metastatic prostate cancer. And you mentioned that there is a distinction among patients who have a positive PET scan and a BCR, and patients who have a positive conventional imaging. And yet, we know that sometimes the findings of the PET scan are not always so clear to interpret. So, I just wanted to understand if the consensus reached an agreement as to when to use conventional imaging to potentially resolve some findings that we have on PET scan among thess patients with BCR? David Einstein: Yeah, I think there's a number of questions actually buried within that question. One of which is: does PSMA PET result in false positives? And the answer has definitely been yes. There's a known issue with false-positive rib lesions. And so, first and foremost, we need to be very careful in calling what truly is suspicious disease and what might actually not be cancer or might be something that is totally separate. So I think that’s the first part of the answer to that question. The second is to what extent do we need to use paired PET and conventional imaging to define this disease state? In other words, do you have to have positive findings on one and negative findings on the other in order to enter this definition? The challenge there, as we discussed, is that logistically, oftentimes it's hard to get patients to do multiple sets of scans to actually create that definition. Sometimes it's difficult to get insurers to pay for such scans. And finally, it's hard to sometimes blind radiologists to the results of one scan in reading the other. So, we did have some deliberations about to what extent you could use some of the CAT scan portion of a PSMA PET in order to at least partially define that. We also talked about using bone scans to confirm any bone findings seen on PET. But I think another important part of this is not just the baseline imaging, but also what's going to be done serially on a study in order to define responses and progression. And that's sort of a whole separate conversation about to what extent you can interpret changes in serial PET. Ravi Madan: And just to pick up on the key factor here, I think that the PSMA PET in BCR is pretty good at defining lymph node disease, and that's actually predominantly 80 to 90 percent of the disease seen on these findings. It might be pretty good at also defining other soft tissue findings. The real issues come to bone findings. And one thing the group did not feel was appropriate was to just define only PSMA-positive bone findings confirmed on a CT bone window. There's not really great data on that, but the working group felt that, when in the rare situation, because it is relatively rare, a PSMA-positive finding is in a bone, a bone scan should be done. And it's worth noting that Phu Tran, who is a co-author and a co-leader of this working group, his group has already defined that underlying genomics of conventionally based lesions, such as bone scan, are more aggressive than findings on next-gen imaging, such as PSMA. So, there is also a genomic underlying rationale for defining the difference between what is seen on a PET scan in a bone and what is seen on a bone scan. Davide Soldato: Coming back to this issue of PET PSMA sometimes identifying very small lesions where we don't see any kind of correlates on conventional imaging or where we see only very little alteration on the bone scan or in the CT scan, was there any role that was imagined, for example, for MRI to distinguish this type of findings on the PET scan? Ravi Madan: So, I think that, again, what can be identified on a PSMA frequently cannot be seen on conventional imaging. We didn't feel that it was a requirement to get an MRI or a CT to necessarily confirm the PSMA findings. I think that generally, we have to realize that in this disease state, that questionable lesions are going to be seen on any imaging, including PSMA. We've actually probably put way too much faith in PSMA findings thus far, as Dr. Einstein alluded to with some of the false positives we're seeing. So, I think that these false positives are going to have to be baked into trials. And in terms of clinical practice, it highlights the need to again, not overreact to everything we see and not necessarily need to biopsy everything and put patients' health in jeopardy to delineate a disease that's indolent anyway. Davide Soldato: Thanks so much. That was very clear. So, basically, the main driver was really also the data showing that if we have a BCR, so a patient with a biochemically recurrent disease that is positive on the conventional imaging, this is usually associated with a different aggressiveness of the disease. But coming back to a comment that you made before, Dr. Madan, you said that even if we talk about PSMA-positive BCR, we are still talking about BCR and the same criteria should apply. So, what we have used for years in this space to actually try to stratify the prognosis of patients is the PSA doubling time, so how quickly the PSA rises over time. So, coming back to that comment, was the consensus on the PSA doubling time basically retained as what we were using before, so defining patients with a doubling time less than 12 months, 10 months, 9 months, as patients with a higher risk of progressing in terms of developing metastatic disease? Ravi Madan: Yes, so that's a very important point. And the working group defined high-risk BCR as a PSA doubling time less than six months. And this really comes from Johns Hopkins historical data, which shows that if your doubling time is three months or less, there's about a 67 percent chance of metastasis at five years. If it's between three and six months, it's 50 percent. And if it's over six months, if it's between six and nine months, it's roughly only 27 percent. There are trials that are accruing with eligibility criteria that they may describe as high-risk that are beyond six months, but the data as really it's been defined in the literature highlights that truly high-risk BCR is less than six months. And the working group had a consensus on that opinion, and that was our recommendation. David Einstein: And I think an important follow-on to that is that's regardless of PET findings, right? And so, we present a couple of case studies of patients with positive PET findings who have a long doubling time, in whom the disease is in fact indolent, as you would have expected from a traditional BCR prognostic standpoint. Obviously, there are patients in whom they have fast doubling times, and even if they do not have PET findings, that doesn't make them not high-risk. Ravi Madan: And just to follow up that point, I will let you know a little bit of a free preview that my colleague Melissa Abel from the NCI will be presenting PSMA findings in the context of PSA doubling time at ASCO GU if that data is accepted. Davide Soldato: Looking forward for those data because I think that they're going to clarify a lot of the findings that we have in this specific population. And coming back to one of the points that we made before, so PET PSMA has a very high ability to discriminate also a very low burden of disease, which we currently refer to as oligometastatic biochemically recurrent prostate cancer, which is not entirely defined as an entity. But what we are seeing both in some clinical trials, which use mainly conventional imaging, but also what we're starting to see in clinical practice, is that frequently we use the metastasis-directed therapy to treat these patients. So, just a little bit of a comment on the use of this type of strategy in clinical practice and if the panel thought of including this as, for example, a stratification criteria or mandated in the design of novel clinical trials in the field of BCR? David Einstein: Yeah, I think that's an incredibly important point. You know, fundamentally, there's a lot of heterogeneity in practice where some folks are using local salvage approaches, some are using systemic therapies, in some cases surveillance may be reasonable, or some combination of these different strategies. We certainly have phase two data from multiple trials suggesting that met-directed therapy may help buy patients time off of treatment until subsequent treatments are started. And that in and of itself may be an important goal that we can come back to in discussing novel endpoints. I think what our panel acknowledged was that, in some sense, the clinical practice has gotten even farther ahead than where the data are, and this is being offered pretty routinely to patients in practice. And so, what became clear was that we, in developing clinical trials, cannot forbid investigators from doing something that would be within their usual standard of care, even if it might not be supported by the most robust data. But at minimum, it definitely should be used as a stratification factor, or in some trial designs, you can do met-directed therapy after a primary endpoint is assessed. And that offers a compromise between testing, say, the effect of a systemic therapy but also not excluding patients and investigators from doing what they would have done had they not been on a study. Ravi Madan: And I would just like to follow up your phrasing in the question of "oligometastatic prostate cancer." We have a figure in the paper and it highlights the fact that, unfortunately, that term in prostate cancer is imaging agnostic. And we've already discussed in this podcast, as well as in the paper, that imaging used to define a metastatic lesion, whether it's PSMA or conventional imaging, carries with it a different clinical weight and a different prognosis. So, we feel in the working group, that the correct term for this disease state of PSMA-positive BCR is just that: PSMA-positive BCR. We also have to realize that when we talk about oligometastatic disease, while it's imaging agnostic, it seems to be numerically based, whether it's five or three or 10 depending on the trial. But PSMA-positive BCR does not have a limit in terms of the number of lesions. And so again, we just feel that there is an important need to delineate what we're seeing in this disease state, which again is PSMA-positive BCR, and that should be differentiated frankly from oligometastatic disease defined on other imaging platforms. David Einstein: Right, and that also makes clear that patients can have polyfocal disease on PET that still is not what we would consider metastatic, but goes beyond the traditional definition of oligometastatic. So, in other words, just because someone has PET-detected disease only, that does not automatically equate with oligometastatic. Davide Soldato: Thanks so much. So, you were speaking a little bit, Dr. Einstein, about the different types of treatment that we can propose or not propose to this patient because you mentioned, for example, that in clinical practice MDT, so metastasis-directed therapy, is becoming more and more used. For these patients, we can potentially use systemic treatments, which include androgen deprivation therapy, which can be given continuously or in an intermittent fashion. And recently, we can also use novel systemic therapies, for example, enzalutamide, to treat this type of patient. So, given that the point of the consensus was really to provide consideration for novel clinical trials in this space, what was the opinion on the panel regarding the control arm? So, if we're looking at a novel therapy in the BCR space, does the control arm need to include a therapy or not? And if so, which therapy? David Einstein: Yeah, this is a super important question and one that's subject to a lot of discussion, especially in light of recent data from EMBARK. What we came to a consensus around was the fact that neither MDT nor systemic therapy should be required as a control arm on BCR trials. And we can talk about a number of reasons for that. There's also the pragmatics of what investigators might actually accrue patients to and what they would consider their standard of care, and that's important to factor in, too. I think that one of the major goals of our working group was outlining what kinds of trials we would like to see in the future and where the limitations of the current data stand. For example, EMBARK proposes a strategy of a single treatment discontinuation and resumption at a predefined threshold indefinitely. That's probably not how most people are practicing. Most folks are probably using some version of intermittent therapy as they would have before this trial, but we actually don't have any data supporting that. Moreover, we don't have data comparing different intermittent strategies to one another. We don't know what the right thresholds are, we don't know how much time we buy patients off treatment, and we don't know to what extent MDT modifies that. And so, those are all really important questions to be asking in future versions of these trials. I'd say my second point would be that a lot of drug development is happening with novel therapies that are not hormonal, trying to bring them into this space. And when you think about trying to compare one of those types of therapies to a hormonal therapy on short-term endpoints, the hormonal therapy is always going to win. Hormonal therapy is almost universally effective, it will bring down PSAs, and it will prolong, quote-unquote, "progression." The downside of that is that hormonal therapy doesn't actually modify the disease, it suppresses it, and it tends to have fairly transient effects once you remove it. And so, part of our goal was in trying to figure out some novel endpoints that would allow these novel types of therapies to be examined head-to-head against a more traditional type of hormonal therapy and have some measurement of some of the more long-term impacts. Davide Soldato: So, jumping right into the endpoints, because this is a very relevant and I think very well-constructed part of the paper that you published. Because in the past we have used some of these endpoints, for example, metastasis-free survival, as potentially a proxy for long-term outcomes. But is this the right endpoint to be using right now, especially considering that frequently this outcome is measured using conventional imaging, but we are including in these trials patients who are actually negative on conventional imaging but have a positive PSMA when they enter this type of trial? David Einstein: Yeah, there's a number of challenges with those types of endpoints. One of which is, as you say, we're changing the goalposts a little bit on how we're calling progression. We still don't... /episode/index/show/jcopodcast/id/40050855

Association Between EOL SACT and Healthcare Utilization 01/08/2026

Association Between EOL SACT and Healthcare Utilization Host Dr. Davide Soldato and guests Dr. Kerin Adelson and Dr. Maureen Canavan discuss JCO article ",” highlighting adverse outcomes for patients who receive any type of systemic anticancer therapy(SACT) at EOL (end of life) and the need for better communication between oncologists and patients regarding expected risk and benefits of such treatments to properly align goals-of-care. TRANSCRIPT Dr. Davide Soldato: Hello and welcome to , the podcast where we sit down with authors from some of the latest articles published in the . I am your host, , medical oncologist at Ospedale San Martino in Genoa, Italy. Today, we are joined by authors Dr. Maureen Canavan, epidemiologist and associate research scientist at Yale Cancer Outcomes, Public Policy and Effectiveness Research Center; and by Dr. Kerin Adelson, Chief Quality and Value Officer, medical oncologist, and clinical researcher on health services and clinical care delivery at MD Anderson Cancer Center. In the manuscript "." that you recently published in the , you performed an analysis that included more than 30,000 older adults in the SEER-Medicare database, and you observed that 7.6% of these patients received any systemic anticancer medication within 30 days of death. So, I wanted you to explain why you thought that this was a priority right now, and whether there was any previous data that was published in the literature, and if you think that there was any significant gap in the literature that led you to the research you just published. Dr. Kerin Adelson: We have published a series of articles looking at real-world trends in patterns of care, particularly related to systemic anticancer therapy at the end of life. This has been gaining increasing focus in recent years because of the understanding that when patients stay on systemic anticancer therapy, that is often a surrogate for a lack of goal-concordant care. So, patients who continue to receive systemic therapy have worse quality of life, are more likely generally to have a medicalized death, and less likely to use hospice. And what our prior work has shown is that more and more we are seeing patients using immunotherapies and targeted therapies towards the end of life. No prior work had really comprehensively examined whether these novel therapies were associated with those same patterns of care increases in acute care utilization and decreases in hospice. Dr. Davide Soldato: So basically, the data that we had up until that point was mostly with cytotoxic chemotherapy, and the emergence of this new treatment, which frequently are thought to be less toxic and so less problematic also in the end of life, led to this research. Is that correct? Dr. Kerin Adelson: Correct. Dr. Maureen Canavan: I would also build on that. I think that as the landscape of cancer care changes, it is important to really understand the availability of treatments, but then also, as Kerin noted, it is important to focus on goal-concordant care. We have established literature, studies we have done and some other studies that have looked at cytotoxic chemotherapy, but with the emergence of these targeted therapies, we really did not know a few things. We did not know the rates of utilization in a large national population, and how that was associated with these elements of medicalized death like ED use, hospitalizations, acute care use. So this was really a question that we had going into it. How can we expand the knowledge base so that both patients and providers can be more cognizant when thinking about goals of care conversations and ensuring that that is in place? Dr. Kerin Adelson: And our work has kind of evolved to answer some critical questions. So, one of our early papers looked at different rates of systemic anticancer therapy at the end of life, and that is where we showed that we were seeing a lot more immunotherapy and targeted therapy. And then we asked the question, well, oncologists generally when they give these treatments, they are hoping that those treatments are going to work and help the patients live longer. So we did another paper where we actually looked at practices who were more aggressive near the end of life and whether they had better overall survival than practices that were less aggressive, accounting for the fact that there could be populations of patients who benefited. And in fact, we showed there was no survival difference. So then this paper sort of answered the question: Well, if it is not having benefit, is this treatment actually doing harm? And this study gets at that question: What are the harms of continuing patients on therapy past the point of benefit? Dr. Maureen Canavan: And I think building off of that, the use of the SEER-Medicare database is a quite robust database. So in this, we have very specific data we can track. We can track the exact type of treatment they had, you know, was it a targeted therapy? Was it immunotherapy? So looking at those subclasses of therapy. We were also able to directly link it within that time frame to the acute care utilization, a limitation that we had in some of our previous work that that data was not always available. So it is more focused in the sense that we were looking at older adults, so patients 66 years of age and older, but we were able to get those individual metrics. So to Kerin's point, we did not see the survival benefit. What do we see then for these medicalized death elements? So the higher rates of all of them across the board. Dr. Davide Soldato: So coming back to the cohort and to the data that you utilized, Dr. Canavan mentioned the use of the SEER system to analyze these data. You already mentioned that you included mostly older adults, so those aged 66 and more. And also there was a little bit of restriction regarding the fact that the patient needed to be covered by Medicare in the last year of death concerning Part A and Part B, and the last 30 days from death concerning Part D. So I just wanted to ask a little bit of a question regarding these findings and whether you think that we also need additional work, especially in the younger population because I think it is something that all of us who work in oncology have seen. The aggressiveness, and this is also something that you showed in your data, tends to increase as the age of the patient tends to decrease. So we tend to be more aggressive towards younger patients. So just a comment on that on the population and generalizability of the findings. Dr. Maureen Canavan: Yeah, I will start with the data question element. Thank you. I think there are a few things to point out for that. So in terms of the restriction to ensure that they had continuous Part D coverage, that was necessary for us to track their oral medication use during that time. So kind of an easy response. The Part A, Part B requirement, it is actually pretty widely used in studies of SEER-Medicare data, and that is you want to establish the patient population, that they are not getting treated with another insurance provider in some way that you are not able to track. So that ensures that we can track not only their systemic anticancer therapy use but also when we are trying to make sure that we are controlling for confounders like chronic conditions and stuff, we are able to track the presence of chronic conditions. So we wanted to make sure we were not biasing the data, so I think that was an important consideration. You do point out very wisely that there are then limitations with the generalizability, and I think we would be lacking if we did not account for that. But I think it is important to establish this baseline relationship association, and then you can step out, we will say, to more diverse populations. So I think we could potentially maybe try to relax the timeline to see if people that might have influx in and out of the Medicare system are still seeing those same rates. I think it is likely they would. But I think to the bigger point that you bring up is that establishing this within the older adults where, you know, we do see as they get older maybe less rates of systemic therapy, extending it to the younger population. There is a challenge with that in that just that data is not available to the robust level that SEER-Medicare is. Both Kerin and I have noted that there is the possibility to look within one specific insurance provider type. Again, recognizing the limitations of the generalizability, but always slowly pushing the needle, finding out more about younger adult populations. And I think this is maybe in an ideal world, but setting the precedent that we really do need to track this on a national scale within younger adults because they do have the need. We do see these higher rates of utilization, and really making sure again with the mindset always of the best interest of patients and the most informative to providers in how we are looking at care. So I think generalizability is definitely a goal. However, there are limitations of the availability of data for younger populations and I think that they are a necessary restraint that all researchers should acknowledge. Dr. Kerin Adelson: Yeah, I think it is important for our audience to understand that health services research and large database research is really limited by what databases are available and what are the characteristics of those databases. So we have done a lot of work in an electronic health record database, and there you can get certain kinds of granularity that you may not be able to get in a payer or a claims-based database. But what you do not get is that comprehensive look at, say, what happens if a patient goes to another practice. Claims-based databases offer you that, but research on US populations is limited by our payment system. So when you look at younger patients, there are so many different insurance companies that when you are trying to get that comprehensive view, it can be hard or very expensive actually. These commercial insurers will sell their data to different databases. So for us, the largest single payer in the United States is the US government, and that is for patients who are over age 65, and that is why you see lots of US-based studies done in the Medicare population. Interestingly, a recent paper by a Canadian group showed very, very similar patterns. It was a significantly smaller study but, right, Canada is a single-payer system and so they were able to really look at all ages, and we did see the same patterns of care in a different payment system. Dr. Davide Soldato: Going back a little bit to the type of treatments that were observed in your manuscript, so we start from a 7.6% of patients who received any type of systemic anticancer therapy within 30 days from death. And when we split the different categories that you analyzed, which I think is a very strong aspect of your manuscript, we see that more or less 50% of the patients received chemotherapy, 20% more or less received immunotherapy, more or less 20% targeted therapy, and then there is a combination of those agents. So just wanted to have a little bit of your opinion compared also to the data that you already published and that you mentioned before. Was this in line with previous data? Was there anything surprising about this? We saw a little bit of a raise in the use of immunotherapy and targeted therapy as you were saying, but still, there is a very high proportion of chemotherapy, 50%. Dr. Kerin Adelson: So I think that really, really reflects the time period in which we studied where immunotherapies were gaining ground. There was tons of excitement and we were seeing this shift. I bet if we do the same study in five years that chemotherapy percent may even go down to half, and we are going to see more and more targeted and immunotherapies, and that is just reflecting the pattern of drug discovery that we are seeing. Dr. Davide Soldato: Coming to the real question that you wanted to answer with this manuscript, so is systemic anticancer therapy associated with worse outcomes in terms of healthcare utilization and use of hospice resources? Was there any hint that for example immunotherapy was related to less of these adverse outcomes? Dr. Kerin Adelson: So I will be honest, I was a little bit surprised that the combination of chemotherapy and immunotherapy was that much more strongly correlated with acute care use at the end of life. You know, I had really thought most likely that what we would see were similar rates. And we did. Each different type of systemic anticancer therapy was associated with significantly higher odds of ending up in the hospital, going to the ICU, dying in the hospital, going to the ED. But that group that got dual therapy was that much higher, you know, over three times the risk. And that surprised me because what it suggested is that there is likely a component of treatment toxicity that is leading to some of the acute care use. It is not simply just a constellation of patients who have not yet transitioned towards hospice or palliative care or end-of-life care who are then more likely to end up in the hospital. But the fact that we see a difference between, say, single-agent immunotherapy and dual combination with chemotherapy does suggest that the treatments are actually contributing to some of what we are seeing. Dr. Davide Soldato: But still, all of the treatments that you evaluated were still associated with higher healthcare utilization. Like there was no signal that, for example, giving immunotherapy at the end of life was not associated with these adverse outcomes. Correct? Dr. Kerin Adelson: Correct. And you will find oncologists out there who will say, actually, these treatments are so good that they might actually lower rates of hospitalization because they keep patients healthy. And certainly, that may be true upstream or earlier in the course of disease, but at the end of life, any form of systemic anticancer therapy is really a surrogate marker for lack of transition towards what is likely appropriate end-of-life therapy. And I just want to point out that time spent in the hospital, going back and forth to invasive procedures, going to the intensive care unit, even going back and forth to an infusion center, that is time that is not spent at home with loved ones for people who have very little time left to live. Dr. Davide Soldato: Thank you very much. That was exactly the point that I wanted you to stress because I think it is really the most important message that we can get as oncologists from this manuscript. Like there is no treatment that is not associated with potentially harming our patient and, as you were saying, taking off time with loved ones in a critical period of the life of these individuals who have been diagnosed and treated for cancer. So, basically what we saw in the paper was a 7.65% utilization of systemic anticancer therapy. And I might imagine that for some oncologists or for some hematologists that might not actually be that much. Like they could potentially say, "Okay, but it is like 7%, it is not that high. I would have expected something higher." So I just wanted a little bit of perspective regarding also quality metrics that we have available for these types of indicators at end-of-life care. What would be the appropriate percentage of people receiving any type of treatment within 30 days from death? Dr. Maureen Canavan: A couple caveats, as a data person I always like to give those. This was among all cancer patients, so not necessarily patients that had been on active treatment. So I think that number was actually quite lower than when we looked in another study about patients that had chemo within the last year, so on, you know, active treatment. So I think that is an element to take into consideration is that those numbers will vary based on who your denominator population is. So that is important to consider. Additionally, the National Quality Forum, they call for reducing rates of systemic therapy at end of life. But I think they, similar to how I would be, are cautious to point out this is the exact number, or it should be zero. Because there are cases where you have to go in line with patient preferences. And if a patient is very adamant that they want to continue treatment, that needs to be a decision that comes between them and their provider. So, you know, the zero, though sounding ideal to us who want to encourage transitions and encourage goals of care conversation is a nice number, it is not a realistic. So, to evade your question completely, I do not think there is a set number. But the goal is to make sure that both patients, providers, everyone is informed and is making the best holistic decision. So there is this natural tendency, I think, to keep fighting both for the patient and the provider to try to beat something, but recognizing the point at which we are beyond a benefit of treatment and what would be most beneficial to the patient in terms of getting back to that idea of, you know, the time with their families and whatnot. So is the number zero? No. Could it probably be lower than we have? I think yes, definitely. Dr. Kerin Adelson: I completely agree with everything Dr. Canavan said. I think one of the other challenges is that this data isn't being tracked and publicly reported across the world. And so what that optimal rate is, is a little unclear. We see different rates also depending on the population included. So one of the things Dr. Canavan said is our database included patients who were likely treated long ago for cancer and cured of their cancer. So they were less likely to die on systemic therapy. But until everybody starts tracking and reporting, it is really hard to know where we are as a country or really as a global population, and then what are the bars that we want to achieve in driving down the rates. I think some data shows that probably something in the range of 10% or below, you know, for patients who have more active cancer is probably where we should be going and driving towards. But until we have more public reporting of these metrics and consistency in how we measure them, it is really hard to come up with a single number. Dr. Davide Soldato: I have the impression that sometimes there is also a little bit of difficulty for the oncologist or the hematologist to really understand who are the patients who are approaching end of life. So there has been some data and you also report some of them in the discussion of the manuscript regarding, for example, prompts inside of the electronic health records or the use of artificial intelligence to try to predict what is the disease course. So just wanted a little bit of perspective if you think that these tools could potentially be helpful and if you think that we will be able at a certain point to implement them in routine clinical care. Dr. Kerin Adelson: I have been working on trying to do this actually at MD Anderson and coming up with a really reliable data tool that will tell us who are the patients who are going to die in short order after receiving systemic anticancer therapy. And it is not that easy, I will say. So, you know, I think we all want this amazing machine learning model that is incredibly reliable. But like any statistical test, there are problems, right? So a very sensitive test that is going to identify high, high risk of dying at the end of life is going to be compromised by false positives. And when an oncologist knows that the test might be a false positive, it becomes very hard for them to take action on it. Similarly, you know, a very, very specific test is going to be compromised by false negatives. So in that case, you could end up having patients who are at risk for dying and still treating them with chemotherapy. And so, you know, I think in the end we need some tools. It will be... /episode/index/show/jcopodcast/id/39619710

Milan Consensus Endpoints for Bladder Preservation in MIBC 12/11/2025

Milan Consensus Endpoints for Bladder Preservation in MIBC Guests Dr. Andrea Necchi, Dr. Ashish Kamat and host Dr. Davide Soldato discuss JCO article ",” focusing on the evolving treatment landscape of MIBC (muscle-invasive bladder cancer) and the need to properly design novel trials investigating non-operative management while including the incorporation of biomarkers and patient perspectives in clinical trials. TRANSCRIPT The disclosures for guests on this podcast can be found in the show notes. Dr. Davide Soldato: Hello and welcome to , the podcast where we sit down with authors from some of the latest articles published in the . I am your host, Dr. Davide Soldato, medical oncologist at Ospedale San Martino in Genoa, Italy. Today we are joined by authors Andrea Necchi, Associate Professor of Medical Oncology at University San Raffaele and Medical Oncology at Ospedale San Raffaele in Milan, Italy, and Ashish Kamat, Professor of Urologic Oncology and Cancer Research at University of Texas MD Anderson Cancer Center. Both Professor Necchi and Professor Kamat are internationally recognized experts in the field of genitourinary malignancy and particularly in bladder cancer. Today we will be discussing the article titled "." So thank you for speaking with us, Professor Necchi and Professor Kamat. Dr. Andrea Necchi: Thank you, Davide, and thank you for the opportunity. Dr. Ashish Kamat: Yeah, absolutely. It is a great honor and privilege to be discussing this very important article with you. So thank you for the invitation. Dr. Davide Soldato: The article that you just published in reports the results of a consensus meeting that was held among experts in the field of genitourinary malignancy and particularly for bladder cancer. So the objective was really to define endpoints for a novel generation of trials among patients diagnosed with muscle-invasive bladder cancer. So my first question would be: what is the change in clinical practice and in clinical evidence that we have right now that prompted the start of such consensus in 2025? Dr. Andrea Necchi: So, we are living so many changes in the treatment paradigm of patients with muscle-invasive bladder cancer. In general, patients diagnosed with bladder cancer or urothelial cancer today, thanks to the advent of immunotherapy or immunotherapy combinations, and today thanks to the advent of novel antibody-drug conjugates like enfortumab vedotin in combination with immunotherapy that are actually changing the landscape of treatment of patients with metastatic disease and also are entering quite fast into the treatment paradigm of patients with organ-confined disease with a lot of clinical trials testing these combination therapies, neoadjuvantly or adjuvantly, before or after radical cystectomy. Having said that, by potentiating the efficacy of systemic therapy, an increasing number of patients that receive neoadjuvant therapy of any kind, at a certain point in time, result to have achieved a deep response to systemic therapy, evaluated radiologically with conventional imaging, CT scan or MRI, or with cystoscopy or with other urology-based techniques, urinary cytology, and so. And based on the fact that they achieve a complete response, so no residual viable disease after systemic therapy, they raise concern about the fact that they have to undergo surgery like radical cystectomy that is quite impactful for their quality of life and for the future of their lives after the surgery. So the point that the patients are raising, and the patients are raising this point, is primarily due to the efficacy of systemic therapy. And we have seen so many cases fortunately achieving a deep response. So the question about what to do with the patient that at a certain point, at the start with the commitment to radical cystectomy, but at a certain point in time change their mind towards something else if possible, depending on the fact that they have achieved a deep response, is something that is a question and is a need to which we have to provide data, information, and guidance in general to the patients. Dr. Davide Soldato: If we look at the population that the recommendations were formulated for, we are mainly speaking about patients who would be fit for cystectomy, and this is a very distinct population compared to those who are not fit for cystectomy, both from a medical oncology point of view but also from a urologic point of view in terms of surgery. So, can you explain a little bit to our listeners why you think that this distinction is critical and why you developed this recommendation especially for this population? Dr. Ashish Kamat: That is a very important distinction that you made. To build upon what Professor Necchi mentioned earlier, this question that we get from patients after neoadjuvant therapy or systemic therapy is not a new question. It has been something that they have been asking us for the last 20 or 30 years. "Do I really need to have my bladder taken out?" And patients who are especially not fit for surgery will sometimes say, "Do I need to have my bladder taken out? And if I cannot have my bladder taken out, am I going to just not have anything done?" Because the eligibility for radical cystectomy is also a moving target. Over the years with improvement in surgical technique, improvement in perioperative therapy, ERAS protocols, et cetera, it is really unusual for us to deny a patient the opportunity to have major surgery unless clearly they have very significant comorbid conditions. So I think this endeavor is more broadly encompassing of the patient population than what was evident in previous years. And I really want to give a shout out to Professor Necchi because what we did was, as part of the International Bladder Cancer Group and Professor Necchi is an integral part of the scientific advisory board, we broached this topic broadly during one of our discussions. And of course, Andrea always does this, he picks on a topic and then he says, "Okay, we need to discuss this really in detail," put together a multinational, multicenter collaborative group, but the driving force was our patients. Because our patients are constantly asking, "Do I need to lose my organ? Do I need to have radiation therapy?" which again, also, has a lot of side effects. So this was really to answer the question in today's day and age as to do we need to do local consolidation, and if so, in what way? It is not a new question, but we have newer therapies, newer technology, and better ways to answer this. So it is a much needed question that needs to be answered. And I think the distinction between non-surgical candidates and surgical candidates is a little bit blurred in today's day and age. Dr. Davide Soldato: What about the eligibility, for example, for cisplatin-based chemotherapy? Because I think that that is a very fundamental part of this type of strategy that we apply to patients with muscle-invasive bladder cancer. So we know that there are some caveats for proposing such treatment. And also this population was specifically defined inside this recommendation. Dr. Andrea Necchi: I think that the focus of our work is just to analyze what is happening after any type of systemic therapy the patient may get neoadjuvantly. So it is not actually a question of treatment eligibility or including cisplatin eligibility. This is an old question of today's practice and clinical trials. But regardless of what the patient received neoadjuvantly, the point that we have addressed in our consensus meeting was what to do next as a further step after systemic therapy or not. So basically we are- the consensus guidance includes all-comers, so patients to get any type of systemic therapy. So really non-selected based on specific features that determine a special eligibility to a special or a particular therapy. But an all-comer approach is always the winning approach for the translation to be in practice, an all-comer approach just focusing on what has happened after treatment and that we are assessing by the use of conventional imaging, MRI or CT, cystoscopy, urinary cytology, and trying to merge all together this information, all these features in a unique, shared, reliable definition of clinical complete response that could be used as a biomarker for the selection of newer therapies instead of pathological response that has been historically used, and maybe surrogate for the outcome, the long-term outcome and survival of these patients. Dr. Davide Soldato: A very specific point of the consensus was actually the definition of clinical complete response. As you were saying, this is actually a combination of several parameters including urinary cytology, the use of cross-sectional imaging, for example CT scan, but also the evaluation in cystoscopy of the bladder. Do you foresee any potential problems when applying this type of recommendation, not inside clinical trials, but in the context of routine clinical practice? Dr. Ashish Kamat: Absolutely. And that was the whole reason we had this consensus meeting. What happens nowadays in daily practice, and we see this every day at our center, we see patients referred to us. This definition or this sort of attempt to define clinical complete response is an ongoing issue. And urologists, medical oncologists, radiation oncologists are always looking to see, does my patient have a complete response? That definition and those paradigms have changed and evolved over the years. The FDA had a workshop many years ago looking at this very question. And it was to address the proposal that complete clinical response, which is a clinical definition, a clinical state, does this correlate with pathologic response? And with the technology and the systemic therapies we had then, the answer was ‘no’. In fact, more patients got recurrent disease than did not get recurrent disease. And that is why, of course in the paper we mention the trials that looked at this question, the trials that evolved around this question. And I think the distinction between a clinical trial and daily practice is extremely important when we are looking at this definition per se. Because essentially what happens with this issue is that if the patient is not appropriately counseled, and if the physician does not do the appropriate clinical complete response assessment as Professor Necchi mentioned, right, cystoscopy, cytology, imaging, use of markers that are still in evolvement, we risk doing harm to the patient. So we caution in the paper too that this definition is not ready for prime time use. It is something that needs to be studied. It is a rigorous definition and currently we are recommending it for clinical trials. I am sure eventually it will trickle down into clinical practice, but that guidance was not the purpose of this consensus meeting. Dr. Davide Soldato: There are several parameters that are potentially evolving and could potentially enter inside of clinical practice. For example, you mentioned pelvic MRI and we have now very specific criteria, the VI-RADS criteria, we’re able actually to diagnose and also to provide information. So along with these novel imaging techniques, we also know that there are novel biomarkers that could be explored, for example ctDNA and urinary DNA. So what I was wondering is, why were not these included inside the definition that you provide for clinical complete response? And do you think that, as we are designing these trials to potentially spare cystectomy for this patient, we should include these biomarkers very early so that we can actually provide better stratification for our patients and really propose this type of cystectomy-sparing strategy only to those where we are very confident that we have obtained a clinical complete response? Dr. Andrea Necchi: I would say you have just to wait. So a follow-up is ongoing and hard work is ongoing. At the time we met, at the time we established the meeting in mid-December last year, we had no information on the ctDNA data from major trials, with only a few exceptions. So we were just at the beginning of a story that was more than likely to change but still without numbers and without data from clinical trials. Now in just nine months or 10 months time, we have accumulated important data and newer data will be presented during just a few weeks and a few days regarding the ctDNA, circulating tumor DNA in particular, as a prognostic marker assessed baseline or assessed after neoadjuvant therapy. So the point is certainly well made and ctDNA is certainly well shaped to be incorporated in a future definition of clinical complete response. But you have to consider the fact that most of the data that we are accumulating related to ctDNA are about the post-cystectomy field or the metastatic field. So regarding neoadjuvant therapy, you know, we have neoadjuvant therapy in the context of bladder-sparing approach, basically we have no information. And the point that is emerging in our daily practice when using these biomarkers or in clinical trials, and the impression in general, is that it is a very strong biomarker associated with survival, but we absolutely do not know what is the performance of the test in the prediction of superficial bladder relapses, high-grade pTa relapse in the bladder that is left untouched in the patient. We are considering, and maybe it will be just a matter of further discussion, not just what is happening within the immediate endpoint of clinical CR, but also what is happening later with other survival endpoints. And for example, when looking at the type of events that we may see in this kind of bladder-sparing approaches, most of the events, also in the trials that have been published including the RETAIN study published in , most of the events are related to superficial high-grade superficial non-muscle invasive relapses. So the ability to predict these types of events with ctDNA is completely unknown. Maybe, maybe other liquid biomarkers like urinary tumor DNA, utDNA, could be a bit better shaped in the prediction of this kind of events, you know. But we have still to build the story. So the question is good. The answer is yes, we will likely, more than likely incorporate liquid biomarkers in the definition, but we have to wait at least more data and more robust data in order to translate this information in routine practice, you know. Another consensus meeting is organized by IBCG and the same folks for November. This meeting will be primarily focused on the liquid biomarkers, the interpretation and use and approval and so of liquid biomarkers including bladder cancer. And we will likely be able to address all these, most of these open issues, so most of these points in the next meetings. Dr. Davide Soldato: In the consensus you say that probably clinical complete response is now ready to be included in early phase trials, so actually to test what is the efficacy of the regimens that is being evaluated inside of these trials. But you actually do very in-depth work of defining what are the most appropriate endpoints for later phase trials. So to be very specific, the phase three registrational trials that bring new regimens inside of this space. So I just wanted to hear a little bit about what was the definition for event-free survival, which you define as the most appropriate one for this type of trials. And as you were mentioning before, Professor Necchi, there is a very specific interest on the type of events that we observe, especially when we look at these superficial relapses inside of the bladder. So was this a very urgent matter of debate as we define which type of events should actually trigger event-free survival? And did you make a very thoughtful decision about why using this type of endpoint instead of others, for example metastasis-free survival? Dr. Ashish Kamat: Yeah, this was a matter of intense debate as you might imagine. And again, this is a moving target. So as Professor Necchi mentioned, we tend to partner with each other, our organizations, on having definitions of clinical complete response, biomarker, retreats, and then using that as a marker, and you might imagine this definition of what is appropriate event-free survival, what events matter to the patient, is something we have been talking about for two years. It was not just something that came up at the retreat. But at the retreat there was intense discussion. One of the things that we talked about was bladder-intact event-free survival because we are trying to spare the patient's bladder. And do we count bladder-intact event-free survival as something that is relevant? The patient advocates absolutely liked that, right? They wanted that. But then we also learned from some of the studies, for example from the RETAIN study, that the non-muscle invasive recurrences can actually lead to metastatic disease. It is not as benign when you have a patient with muscle-invasive bladder cancer that then develops a non-invasive tumor because maybe there is cancer growing underneath the surface that we don't detect when we look in the bladder. So a lot of those discussions were held, debated. It was a consensus. I have to say it was not 100% agreement on that particular definition, but it was broad consensus. And Andrea, do you want to clarify a little bit as to how we came about that consensus? Because I think this is a very important point we need to make. Dr. Andrea Necchi: We focused on a bit different definition of BI-EFS, Bladder-Intact Event-Free survival. Just stating EFS as an all-inclusive parameter including all type of high-grade relapse or progression or death that may happen to the patient. So that we were counting high-grade pTa, pT1, CIS relapses to the bladder and of course more deeper involvement in the muscle layer and so, and metastatic disease as a relapse. But the point is that as compared to the classical bladder-intact EFS definition of chemoradiation bladder-sparing approaches that is including muscle-invasive relapses only or death as events, we tried to be as inclusive as possible in order to be as much conservative as possible and to raise as higher the bar as possible for the success. And this is actually what the patients are asking us. So they are asking, "Okay, I can save my bladder, sparing radical cystectomy, but at which cost?" So in order to provide an answer, we have to be very, very cautious and be on the right shape, on the right position to say, "Okay, we have accomplished the most, the safest points, you know, by which you can proceed with the bladder-sparing." This is the first point. The other point is related to the MFS, metastasis-free survival that you have mentioned. For sure, it was recognized as a very important point for sure. But in the discussion was clear that our focus was in saving patients, curing the patient, and saving the bladder. Any single event, superficial event that may occur in the bladder-saving approaches of this kind may expose the patient to an extra risk of developing distant metastases, as it happened for example in the RETAIN study. So EFS defined as we have agreed and published, is actually a way of including or anticipating in a safest position the MFS. Because most or if not the entirety of the events of metastasis development in patients undergoing bladder-sparing after neoadjuvant systemic therapy were preceded by a superficial phase of disease relapse, you know. So I remember very, very few, or we can count just on the finger of one hand, the cases that have been reported in the literature developing de novo metastatic disease in the similar bladder-sparing approaches, in particular when using a maintenance immunotherapy strategy, you know, after they reach TURBT. So this is the reason why with all the limitation that Ashish has mentioned, with all the uncertainties that are still there, the nervousness that is still there, EFS, as... /episode/index/show/jcopodcast/id/39328500

JCO at 2025 ASH: Pirtobrutinib in Untreated CLL 12/09/2025

JCO at 2025 ASH: Pirtobrutinib in Untreated CLL JCO Editor-in-Chief Dr. Jonathan Friedberg is joined by colleagues Dr. Jennifer Woyach, Dr. Wojciech Jurczak, and Dr. Matthew Davids to discuss simultaneous publications presented at ASH 2025 on pertibrutinib, a new upfront treatment option for patients with chronic lymphocytic leukemia. TRANSCRIPT The disclosures for guests on this podcast can be found in the show notes. Dr. Jonathan Friedberg: I’m Jonathan Friedberg, editor of , and welcome to , where we are covering two manuscripts that were presented at the meeting 2025 in Orlando, Florida. I am delighted to be joined by colleagues on this call to discuss these pivotal manuscripts which cover the topic of pirtobrutinib, a new upfront treatment option for patients with chronic lymphocytic leukemia. I will first just introduce our guests, Dr. Woyach. Dr. Jennifer Woyach: Hi, my name is Jennifer Woyach. I am from the Ohio State University. Dr. Wojciech Jurczak: Hello, I am Wojciech Jurczak, working at the National Research Institute of Oncology in Krakow, Poland. Dr. Matthew Davids: Hi, I am Matthew Davids from Dana-Farber Cancer Institute in Boston. Dr. Jonathan Friedberg: We are going to start by just learning a little bit about these two trials that were both large, randomized phase 3 studies that I think answered some definitive questions. We will start with your study, Jennifer. If you could just describe the design of your study and the patient population. Dr. Jennifer Woyach: Absolutely. So this is the . The patients were both treatment-naive and relapsed/refractory, about one-third of the patients treatment-naive, the rest relapsed/refractory, and they were stratified based upon 17p deletion and the number of prior lines of therapy. The primary objective was looking at non-inferiority of overall response rate over the entire treated population as well as the relapsed/refractory patient population. Key secondary objectives included progression-free survival in the intention-to-treat and the smaller relapsed/refractory and treatment-naive populations. Dr. Jonathan Friedberg: And just comment a little bit on the risk of the patients. Dr. Jennifer Woyach: This study was fairly typical of this cohort of patients. Within the relapsed/refractory patient population, there was a median of one prior line of therapy in each of the groups, up to nine prior lines of therapy in the patients included on the study. For the overall cohort, about two-thirds of the patients were IGHV unmutated, about 15% had 17p deletion, 30% had TP53 mutations, and about 35% to 40% had a complex karyotype, which is three or more abnormalities. Dr. Jonathan Friedberg: And what were your findings? Dr. Jennifer Woyach: Regarding the primary outcome, which is the focus of the publication, we did find that pirtobrutinib was indeed non-inferior and actually superior to ibrutinib for overall response rate throughout the entire patient population and in both the relapsed/refractory and treatment-naive cohorts. PFS is a little bit immature at this time but is trending towards also being significantly better in pirtobrutinib-treated patients compared with ibrutinib-treated patients. Probably most significantly, we found this to be the case in the treatment-naive cohort where there was a striking trend to an advantage of pirtobrutinib versus ibrutinib. Dr. Jonathan Friedberg: And the follow-up that you have on that progression-free survival? Dr. Jennifer Woyach: So we have about 18 months follow-up on progression-free survival. Dr. Jonathan Friedberg: The second study, Wojciech, can you just go through the design and patient population that you treated? Dr. Wojciech Jurczak: Thank you, Dr. Friedberg, for this question. So the . At the time we designed the protocol, bendamustine-rituximab was an option as a standard of care, and Bruton tyrosine kinase monotherapy was used far more commonly than nowadays. The primary target of the study was progression-free survival. We took all untreated patients except for those with 17p deletions. Therefore, it is a good representation for intermediate risk. We had about 60% of the population, 56 to be precise, which was unmutated, evenly distributed into two treatment arms. 17p deleted cases were excluded, but we had about 7% and 8% of TP53 mutated patients as well as about 11% and 7%, respectively, in the pirtobrutinib and bendamustine-rituximab arm of patients with complex karyotype. The progression-free survival was in favor of pirtobrutinib and was assessed by an independent review committee. What is important is that the progression-free survival of the bendamustine-rituximab arm was actually similar to the other studies addressing the same questions, like the comparison with ibrutinib in the ALLIANCE study or zanubrutinib in the SEQUOIA study. What was different was the hazard ratio. In our study, it was 0.20. It was one of the longest effect sizes noted in the frontline BTK study. It represented an 80% reduction in progression-free survival or death. If we compare it to ibrutinib or zanubrutinib, it was 0.39 and 0.42 respectively. Presumably, this great effect contributed towards a trend of overall survival difference. Although survival data are not mature enough, there is a clear trend represented by three patients we lost in the pirtobrutinib arm versus 10 patients lost in the bendamustine-rituximab arm. This trend in overall survival is becoming statistically significant despite the fact that there was a possibility of crossover, and effectively 52.9 patients, which means 18 out of 34 patients relapsing in the bendamustine-rituximab arm, were treated by pirtobrutinib. Dr. Jonathan Friedberg: I am going to turn it over to Matt. The question is: why study pirtobrutinib in this patient population? And then with these two studies, how do you find the patients that were treated, are they representative of people who you see? And do you see this maybe being approved and more widely available? Dr. Matthew Davids: I think in terms of the first question, why study this in a frontline population, we have seen very impressive data with pirtobrutinib in a very difficult-to-treat population of CLL patients. This was from the original BRUIN phase 1/2 study where most of the patients had at least two or three lines of therapy, often both a covalent BTK inhibitor and the BCL2 inhibitor venetoclax, and yet they were still responding to pirtobrutinib. The drug was also very well tolerated in that early phase experience. And actually, we have seen phase 3 data from the BRUIN 321 study comparing pirtobrutinib to bendamustine and rituximab in a relapse population as well. So I think that really motivated these studies to look at pirtobrutinib as a first therapy. You know, often in other cancers of course, we want to use our best therapy first, and I think these studies are an initial step at looking at that. In terms of the second question around the patient population, these are pretty representative patient populations, I would say, for most frontline CLL studies. We see patients who are a bit younger and fitter than sort of the general population of CLL patients who are treated in clinical practice, and I think that is true here as well. Median age in the sort of mid-60s here is a bit younger than the typical patients we are treating in practice. But that is not different from other CLL frontline studies that we have seen recently, so I think it makes it a little bit easier as we kind of think across studies to feel comfortable that these are relatively similar populations. Dr. Jonathan Friedberg: How do you see this either getting regulatory approval or potentially being used compared to current standard of care options? Dr. Matthew Davids: So my understanding is that both of these trials were designed with registrational intent in the frontline setting, and they are both positive studies. That is certainly very encouraging in terms of the potential for an approval here. We have seen in terms of the FDA recently some concerns around the proportion of patients who are coming from North America, and my understanding is that is relatively low on these two studies. But nonetheless, the datasets are very impressive, and so I think it is certainly supportive of regulatory approval for frontline pirtobrutinib. Dr. Jonathan Friedberg: I will ask Jennifer a question. The control arm in your study was ibrutinib, and I think many in the audience may recognize that newer, second-generation BTK inhibitors like acalabrutinib and zanubrutinib are more frequently used now if monotherapy is decided. How do you respond to that, and how would you put your results in your pirtobrutinib arm in context with what has been observed with those agents? Dr. Jennifer Woyach: Yeah, that is a great question. Even though in the United States we are predominantly using acalabrutinib or zanubrutinib when choosing a monotherapy BTK inhibitor, this is actually not the case throughout the entire world where ibrutinib is still used very frequently. The head-to-head studies of both acalabrutinib and zanubrutinib compared to ibrutinib have shown us pretty well what the safety profile and efficacy profile of the second-generation BTK inhibitors is. So even though we do not have a head-to-head study of acalabrutinib or zanubrutinib versus pirtobrutinib, I think, given the entirety of data that we have with all of the covalent BTK inhibitors, I think we can safely look at the pirtobrutinib arm here, how the ibrutinib arm compares or performs in context with those other clinical trials. And though we really can not say anything about pirtobrutinib versus acalabrutinib or zanubrutinib, I think we can still get a good idea of what might be the clinical scenarios in which you might want to choose pirtobrutinib. Dr. Jonathan Friedberg: And Wojciech, do you agree with that? Obviously, I think you have acknowledged that chemoimmunotherapy is rarely used anymore as part of upfront treatment for CLL. So, I guess a similar question. If you were to put the pirtobrutinib result in your study in context with, I guess, more contemporary type controls, would you agree that it is competitive? Dr. Wojciech Jurczak: Well, I think that that was the last study ever where bendamustine-rituximab was used as a comparator arm. So we should notice that smashing difference. Because if we look at the progression-free survival at two years, we have 93.4% in pirtobrutinib arm versus 70.7% in bendamustine-rituximab arm. Bendamustine-rituximab arm did the same as in the other trials, like ALLIANCE or SEQUOIA. Pirtobrutinib did exceptionally well, as pirto is not just the very best BTK inhibitor overcoming the resistance, but perhaps even more important for the first line, it is very well tolerated and is a very selective drug. Now, if we look at treatment-related adverse events, the discontinuation rate, they were hardly ever seen. If we compared the adverse events in exposure-adjusted incidence, literally all adverse events were two or three times higher in bendamustine-rituximab arm except for the bleeding tendency, which however was predominantly in CTCAE grade 1 and 2 with just 0.7% of grade 3 hemorrhage. Therefore, I think that we should actually put the best and the safest drugs upfront if we may, and pirtobrutinib is, or should be, the first choice if we choose monotherapy. Now, I understand that we are not presenting you the data of pirtobrutinib in combination with anti-CD20 or with BCL2 inhibitors, but that is to come. Dr. Jonathan Friedberg: Matt, how would you envision, were regulatory approval granted and this were an option, using this in the upfront patient population? Is there anybody who you would preferentially use this or start on this treatment? Or would this be something that you would tend to reserve for second line? Dr. Matthew Davids: So I would say that in general for most of my patients who would want to start with a continuous BTK inhibitor, I would still use a covalent BTK inhibitor, and I say that for a couple of reasons despite the very promising data from these studies. The first is that the follow-up for both of these phase 3 trials is still quite short, in the range of a median 18 to 24 months. And we know that CLL is a marathon, not a sprint, and these patients are going to probably be living for a very long time. And we do have much longer follow-up from the covalent BTK inhibitors, median of 10-year follow-up with ibrutinib and five to six years with zanubrutinib and acalabrutinib respectively. And you know, I do not think that the pirtobrutinib is going to fall off a cliff after two years, but on the other hand, I think there is a lot of value to long-term data in this disease, and that is why I think for most of my patients I would stick with covalent BTK inhibitors. But the other important factor that we need to consider is patients who are younger and may have many different CLL treatments over the years. We have to be very careful, I think, about how we sequence these drugs. We know right now that we can start with covalent BTK inhibitors and then subsequently patients will respond well to the non-covalent inhibitor pirtobrutinib in later lines of therapy. But right now we do not have prospective data the other way around. So how will the patients on these studies who progress on pirtobrutinib respond to covalent BTK inhibitors? We do not know yet. There have not been a lot of progression events, which is great, but we would like to see some data in that respect to feel more comfortable with that sequence. Now, I do think that particularly for older patients and those who have significant cardiovascular comorbidities, if they wanted to go on a continuous BTK inhibitor, I do think these data really strongly support using pirtobrutinib as the BTK inhibitor of choice in that population. In particular, the cardiovascular risks with pirtobrutinib seem to be quite low. I was very struck in the comparison with BR that the rate of AFib was equivalent between the two arms of the study. And that is really the first time we have seen that with any of these BTK inhibitors, no elevated risk of AFib in a randomized study. I think that is the population where it will get the most traction first, is the upfront, sort of older patient with significant cardiovascular comorbidities. And as the data from these studies mature, I think that we will start to see more widespread use of pirtobrutinib in the frontline setting. Dr. Jonathan Friedberg: Jennifer, I am just curious if you have any personal experience or heard anecdotally about after progression on pirtobrutinib the use of other BTK inhibitors and whether there is a growing experience there. Dr. Jennifer Woyach: I do not think that there is much clinical experience, you know, as Matt alluded to, it certainly has not been tested yet. There has been some data in relapsed CLL suggesting that in people who have resistance mutations to covalent BTK inhibitors after treatment with pirtobrutinib, sometimes those mutations go away. I think most of us are concerned that they are probably not actually gone but maybe in compartments that we just have not sampled, suggesting that sort of approach where you might sequence a covalent inhibitor after a non-covalent in somebody who had already been resistant probably would not work that well. But, you know, in this setting where people had never been exposed to a covalent BTK inhibitor before, we really have no idea what the resistance patterns are going to be like. We assume they will be the same as what we have seen in relapsed CLL, but I think we just need some longer follow-up to know for sure. Dr. Wojciech Jurczak: If I may confront Dr. Davids about the use of covalent BTK inhibitors upfront, well, I think that we should abandon the idea of using the first and the second and the third generation, at least if we don’t have medical lines. If we endlessly block the same pathway, it is not going to be effective. So if pirtobrutinib gets approval in first, second line, we do not necessarily have to use it in the first line. I am not here in a position to defend that we should treat patients with pirtobrutinib upfront and not BCL2 time-limited regimen. However, the way I look at CLL patients when choosing therapy is not just how should I treat them now, but what would be the best regimen in 5, 10 years if I have to re-treat them. And in some instances, the idea may be that in this setting we would like to have a BTK inhibitor upfront to have a BCL2 inhibitor later to make it time-limited. Although I understand and I agree with Matthew that if we have an elderly, fragile population, then the charm of having a drug taken once a day in a tablet with literally few cardiovascular adverse events might be an option. Dr. Jonathan Friedberg: And I will give Matt the last word whether he wants to respond to that, and also just as a forward-looking issue, I know both investigators have implied that there will be future studies looking at combinations with pirtobrutinib, and if you have any sense as to what you would be looking for there. Dr. Matthew Davids: The field really is heading toward time-limited therapy for most patients, I would say. There is a bit of a discrepancy right now in the field between sort of what we are doing in academic practice and what is done sort of more widely in community practice. And so right now we are going to see evolving datasets comparing these approaches. We are already seeing data now from the CLL17 study with ibrutinib comparing continuous to time-limited venetoclax-based therapy, and we are seeing similar efficacy benefits from these time-limited therapies without the need for continuous treatment. And so that is where I think some of the future studies with pirtobrutinib combining it with venetoclax and other partners are so important. Fortunately, several of these studies are already ongoing, including a phase 3 trial called CLL18, which is looking at pirtobrutinib with venetoclax, comparing that to venetoclax and obinutuzumab. So I am optimistic that we are going to be developing these very robust datasets where we can actually use pirtobrutinib in the frontline setting as a time-limited therapy as a component of a multi-drug regimen. So far, those early data are very promising. Dr. Wojciech Jurczak: Perhaps last but not least, in a single center we have treated over 300 patients with pirtobrutinib. So eventually some of them relapsed. And I must say that our experience on BCL2 inhibitors, not just venetoclax but including sonrotoclax, are appealingly good. Therefore, by using pirtobrutinib even earlier, we do not block the efficacy of other compounds. Dr. Jonathan Friedberg: All right. Well, I want to thank all of our speakers. I also want to at the , and chose to publish them in , so we thank you for that, and - really appreciated. That is this episode of . Thank you for your attention. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Disclosures Dr. Wojciech Jurczak Consulting or Advisory Role: BeiGene, Lilly, Abbvie/Genentech, Takeda, Roche, AstraZeneca Research Funding: Roche, Takeda, Janssen-Cilag, BeiGene, AstraZeneca, Lilly, Abbvie/Genentech Dr. Jennifer Woyach Consulting or Advisory Role: Pharmacyclics, Janssen, AstraZeneca, Beigene, Loxo, Newave Pharmaceutical, Genentech, Abbvie, Merck Research Funding: Company name: Janssen, Schrodinger, beone, Abbvie, Merck, Loxo/Lilly Dr. Matthew Davids Honoraria: Curio Science, Aptitude Health, Bio Ascend, PlatformQ... /episode/index/show/jcopodcast/id/39259810

JCO at ASH 2025: A New Validated Staging System for AL Amyloidosis: AL-ISS 12/07/2025

JCO at ASH 2025: A New Validated Staging System for AL Amyloidosis: AL-ISS JCO Editorial Fellow Peter Li and author Dr. Jahanzaib Khwaja discuss the ASH 2025 Simultaneous Publication article, "." TRANSCRIPT The disclosures for guests on this podcast can be found in the show notes. Dr. Peter Li: Welcome to this episode of JCO Article Insights. I am Dr. Peter Li, JCO’s Editorial Fellow, and today, I am joined by Dr. Jahanzaib Khwaja on . This is a simultaneous publication that will be presented at this year’s ASH Conference. At the time of this recording, our guest has disclosures that will be linked in the transcript. So, Dr. Khwaja, let’s start off first: What would you say is the significance of your study? Dr. Jahanzaib Khwaja: Thank you very much. This is an important study in that, in the current treatment era, we have really improved outcomes of patients with systemic AL amyloidosis. Traditionally, the staging systems that have been employed, which are the Mayo 2012 and the European modification 2016, have been founded in eras where there were historic treatment protocols. So the significance of this new staging system is looking at outcomes of patients in the modern treatment era. That is patients who are treated with daratumumab-based treatments in the first line. And this is kind of the largest study which is externally validating a new prognostic model in the current treatment era with modern outcomes. Dr. Peter Li: Can you tell our listeners what is different about your new staging system? Dr. Jahanzaib Khwaja: The traditional staging systems, the Mayo 2012 and the European modification of 2016, looked at outcomes of patients with systemic AL amyloidosis with historic treatment protocols. And we know that they looked at outcomes according to an NT-proBNP and troponin, and in the Mayo 2012, they looked at it with the addition of the dFLC, which is the difference in the involved and uninvolved free light chain. Over the years, we have seen that outcomes have improved, and over decades, actually, outcomes are much better when we compare them to the previous decade. If we look at current treatment approaches, those traditional staging systems inadequately determine the poorest prognostic risk. So they are unable to tell us those who are going to perform poorly. Our current new validated staging system looks at the traditional NT-proBNP and troponin but uses the addition of the longitudinal strain. This is an echocardiographic parameter, and it is used widely in treatment centers who treat amyloidosis. This really identifies those ultra-high risk patients, and these are the patients who will perform poorly in current treatment protocols. And why is that important? Well, we need a robust staging system in the current treatment era which can stratify patients who will do well but also stratify those patients who do not do well. Because that is important for counseling patients, for risk stratification, for treatment approaches, and in the future, for designing clinical trials. Dr. Peter Li: And that is referring to the longitudinal strain greater than -9% and NT-proBNP greater than 8,500 and then the high-sensitivity troponins greater than 50, which will define the new staging system. Can you talk more about how you picked these cutoffs and also what that alludes to in terms of the outcomes that you have discovered in this age of daratumumab-based therapy? Dr. Jahanzaib Khwaja: Yeah, that is a really excellent question because we have aimed to build upon traditional staging systems. So clinicians have used these traditional models for many, many years, and they have robustly underpinned our stratification of patients and how we counsel patients. So we didn’t want to change some of these well-established thresholds, but we wanted to test them in the current treatment era. So the NT-proBNP of 8,500 and the high-sensitivity troponin of 50 were the traditionally used thresholds. And they actually stand the test of time. But we found that longitudinal strain additionally and independently predicts outcome independent of these other biomarkers. It is independent actually as a continuous variable, so you can cut this at a number of different stratification points and find independence. But we wanted to determine and discriminate those with the poorest outcomes. So we validated a longitudinal strain threshold of greater than -9% by deriving this from a dataset of patients with the traditionally highest risk. Those are with European stage lllB. And looked at the optimal threshold with time-dependent ROC analysis. So we did this in our derivation cohort and then validated this externally in our external validation cohort amongst a number of centers in Europe, in the US, and in the UK. And it is important to note because longitudinal strain is an echocardiographic parameter, and traditionally the limitations are considered to be inter-vendor and inter-operator variability and intra-operator variability, and there are challenges with reproducibility of some of these measurements. So that is often cited as a limitation. But we found, when we have externally validated this across different centers using different platforms, actually the threshold of -9% is independently predictive of poorer outcomes independent of the traditional NT-proBNP and troponin thresholds, and it is robustly predictive of poorest outcomes. We know that those with stage lllC have a median overall survival of 4 to 7 months in the modern treatment era. And if we sub-stratify these by patients treated with daratumumab, outcomes have improved, but still, even if we look at daratumumab-treated patients, one-year overall survival is still only around 50 percent. So these are a poor risk group in the modern treatment era. Dr. Peter Li: Which kind of makes sense in a way because this kind of predicts whether they have amyloid-related cardiomyopathy. So I think this all tracks with our listeners. But given the poor outcomes even with daratumumab-based therapies, do you think this new staging system would change practice, if at all? Dr. Jahanzaib Khwaja: Yeah, I think that is a really good point because I think it comes to the question of why we use a staging system. What are its applications? I think one of the key things we think about in the clinic is how do we counsel patients when we first talk to them about their diagnosis. So there is a lot of information, but predominantly people want to know, what is my outlook going to look like? And as I say, in the bortezomib treatment era, 2010 to 2020, we used to say you have stage lllB, you have very poor outcomes, median survival maybe around six months. We have shown here that actually those with lllB have much better outcomes definitely over 12 months, up to 24 months in those with daratumumab-based therapies. So we need to counsel them in a different way. We then also need to say, “Well, who are the ultra-high risk?” So we said those with the longitudinal strain of greater than -9% with the traditional NT-proBNP and troponin cutoffs. And those patients will have poor outcomes. We need to talk about palliation. We need to talk about alternate treatment approaches. And then importantly for the community is about treatment and clinical trial design. So again, traditionally the traditional high-risk group lllB used to be considered an exclusion for all major trials. So these were excluded in the ANDROMEDA study, which led to the approval of daratumumab-based therapy, and multiple other trials. And we show here that actually patients with lllB should not be excluded from these studies because they do have good outcomes. And I think we make the important point that those with lllC, who do have poor outcomes, they need a different treatment approach, and we need to think about stratifying these patients differently. So perhaps the next modality of treatment will be the anti-fibril antibodies or a mode of treatment which can clear antibodies or clear the amyloid fibrils from the organs and reduce the organ toxicity early on. We know that those with lllC have poor outcomes particularly within the first year, and organ dysfunction really predominates here. So a different treatment approach is required, and we need to design trials specifically for these patients which look beyond anti-plasma cell clone therapy but also look at clearing the amyloid fibrils and improving organ function as this is predominantly the cause of death in these patients. Dr. Peter Li: That’s an excellent point right there. Do you foresee any limitations to this new staging system, or can you comment on is there potentially a better way to refine this staging criteria in the future? Dr. Jahanzaib Khwaja: Yeah, I think that is a really excellent point to consider, that staging systems always need refining across treatment eras. So we have looked at the bortezomib era, and then we have validated this in the daratumumab-based era. We know that amongst different countries access to treatment varies. We know that there are a number of factors which determine your health-related outcomes. That’s access to healthcare, speed of diagnosis, access to tertiary diagnostics, ability to biopsy, and then supportive care. And I think our staging system highlights the importance of organ dysfunction predominantly causing death early on. And I think that as treatments improve this should be refined. So the expectation I think is, as we have better anti-plasma cell directed therapies, and as we hopefully develop anti-fibril antibodies and anti-fibril clearance drugs, that we will need to revalidate new models to effectively prognosticate in this treatment era. And I also think that as we become a bit more sophisticated with our approaches, we know that this can be refined in the future looking at other prognostic factors with regards to healthcare outcomes. I would say one of the strengths, however, of this model is that it builds on the traditional model, and it’s quite simple to use. You just have the NT-proBNP and the troponin, and then longitudinal strain, which is used quite frequently in amyloid centers, and an echocardiogram is used in essentially all patients for diagnosis. So I think it will certainly be quite practical. But certainly I think, as you say, as treatment approaches change over time, and as we have further options in the future, we will need to refine prognostication. Dr. Peter Li: For the listeners out there, let’s say someone comes in our clinic and we diagnose them with stage lllC amyloidosis. Can you comment on what clinical trials are out there that potentially they can refer their patients to? You mentioned anti-fibril therapy, which I think would be the way of the future. Can you kind of comment what you know at this current stage and point listeners in the right direction? Dr. Jahanzaib Khwaja: This is the challenge in amyloidosis. We don’t have specific trials that are looking at those with the highest risk. And at present, even the ISA International Guidelines talk about risk according to the old treatment approaches and discuss attenuating our current chemotherapy approaches. And I think that for clinicians out there who identify those at the highest risk, it is really important to have a multidisciplinary approach, to consider palliation and palliative services early, and really work with your fellow cardiologists and renal physicians and neurologists to enable the best supportive care you have in order to deliver this anti-plasma cell directed therapy. We know that actually you only need for most patients small amounts of doses of chemotherapy to get good clonal responses, and we have seen that even in the bortezomib era that actually they have good CR rates and more impressive CR rates with daratumumab. But because of the organ dysfunction, it can be really challenging to deliver these doses. And supportive care is going to be really important particularly for these challenging patients. The future will be designing clinical trials that are appropriate for these patients. At present, we currently don’t have available options, but I think the more we gather this data, the more we work collaboratively as a community, we will be able to mobilize our resources and get the best outcomes for these patients. Dr. Peter Li: First build the field of dreams and then hopefully more therapies will arrive in the future. Thank you so much, Dr. Khwaja, for speaking about the JCO article, "," and for all your valuable input today. Dr. Jahanzaib Khwaja: Thank you very much. Dr. Peter Li: Make sure to check out the presentation at this year’s ASH Conference taking place from December 6 to December 9. Thank you for listening to JCO Article Insights. Please come back for more interviews and article summaries and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit asco.org/podcast. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. /episode/index/show/jcopodcast/id/39295650

JCO Article Insights: Simultaneous Durvalumab and CRT in Unresectable Stage III NSCLC 11/24/2025

JCO Article Insights: Simultaneous Durvalumab and CRT in Unresectable Stage III NSCLC In this episode of JCO Article Insights, host Dr. Ece Cali Daylan interviews author Dr. Jeffrey Bradley about the article, "" by Bradley, et al published October 13, 2025. TRANSCRIPT Dr. Ece Cali: Welcome to this episode of . This is Dr. Ece Cali, Editorial Fellow. Today I'm joined by Dr. Jeffrey Bradley, Professor of Radiation Oncology at the University of Pennsylvania, to discuss the manuscript, "" The PACIFIC-2 study was a phase III, double-blind, randomized trial comparing the efficacy and safety of simultaneous durvalumab with concurrent chemoradiation followed by consolidation durvalumab to the concurrent chemoradiation followed by placebo in patients with unresectable stage III non-small cell lung cancer. The primary endpoint was progression-free survival by blinded independent central review. The secondary endpoints were overall response rate, overall survival, and safety. Three hundred twenty-eight patients were randomized 2:1 to durvalumab and placebo, respectively. Unfortunately, this trial did not meet its primary endpoint. There were no statistically significant differences in PFS or OS. The frequency of adverse events was similar between the two arms. Grade 3 or higher adverse events were observed in 53% of the patients in the durvalumab arm compared to 59% of the patients in the placebo arm. Of note, the frequency of pneumonitis was similar in the two arms. Approximately 28% of patients in each arm developed pneumonitis, and about 5% of the pneumonitis observed in each arm was grade 3 or higher in severity. Treatment discontinuation rates secondary to the adverse events were higher in the durvalumab arm, 25% compared to 12%. Adverse events leading to treatment discontinuation and death were more frequently seen in the durvalumab arm during the first four months of the treatment, which corresponds to the simultaneous administration of chemoradiation and durvalumab. Dr. Bradley, before we delve into the results, can you please explain the rationale for this study design and how this concept fits into the current treatment landscape? Dr. Jeffrey Bradley: Yeah, this trial came on the heels of PACIFIC after there was a progression-free survival benefit showed in PACIFIC that in the locally advanced unresectable population that consolidation immunotherapy, in this case durvalumab, had a progression-free survival benefit. A number of us in the clinical trial space thought to add concurrent immunotherapy in addition to consolidation immunotherapy that that would also improve outcomes for patients. So a number of trials were launched to follow up of PACIFIC. In this case, this is a phase III trial where the control arm was placebo. There was no overall survival results yet from PACIFIC, just a PFS benefit, and a number of countries across the world had not approved maintenance durvalumab in this space. So this trial looked at the experimental arm, which was concurrent immunotherapy, durvalumab, and chemoradiation followed by consolidation durvalumab versus placebo. Dr. Ece Cali: And if we were to focus on the safety profile first, an increased pneumonitis risk was a theoretical concern when immunotherapy is given concurrently with radiation. Do we see any major differences in the safety profile between the two arms in this trial? Dr. Jeffrey Bradley: No, and we were concerned about the addition of concurrent immunotherapy and chemoradiation, like you said, towards concern about increased pneumonitis rate, but we did not see increased pneumonitis in the experimental arm over placebo. And the grade 3 or higher, as you said, it was roughly 5%, more or less, in both arms, so we didn't see increase in pneumonitis toxicity with concurrent IO and chemoradiation. Dr. Ece Cali: But interestingly though, despite the lack of significantly increased toxicity with durvalumab, unfortunately, administering immunotherapy simultaneously with chemoradiation therapy did not improve survival. Lack of superiority of this treatment regimen, as you mentioned, is further confirmed across multiple similar negative trial readouts such as ECOG-ACRIN 5181 and CheckMate 73L. Dr. Bradley, in your view, what are some potential explanations for why this strategy did not pan out in clinical trials? Dr. Jeffrey Bradley: Regarding toxicity, let me go back and point out that we did see an increased number of immune-mediated adverse events. It was 34.7% in the concurrent immunotherapy arm versus 15.7% in the placebo arm. So that led to a higher number of discontinuations of immunotherapy which I think probably had an effect. So we didn't... there was an increased pneumonitis toxicity, but there were expected immune-mediated toxicities that caused people to stop giving immunotherapy. You can see that in the PFS curves. They were, you know, they crossed over after like a month, but initially there was lower PFS for the experimental arm, and then the experimental arm got better after we divided into four months, before four months and after four months. Dr. Ece Cali: For one reason or another, it looks like the simultaneous administration did not really improve outcomes. We now know that simultaneously giving them another concurrent radiation should really no longer be pursued in clinical trials for this patient population. Can you share with our audience what strategies are being studied in this setting and what trials to watch out for in the future? Dr. Jeffrey Bradley: Sure, I think when you add concurrent radiation to immunotherapy, there were more central tumors in this trial, I think you're killing lymphocytes and negating the effect of immunotherapy. So I think that's the smoking gun for this trial, for the ECOG trial, for the small cell trial that NRG reported, LU005, and other trials. So correct, I don't think there's any need to continue to pursue concurrent immunotherapy in this space of lung cancer. But that's not to say there aren't many other trials that are either ongoing, have accrued and awaiting results, or being planned for the next phase of clinical trials. We have a trial within NRG Oncology called NRG-LU008. It's a randomized phase III trial that is using an SBRT boost to a peripheral primary and chemoradiation to the nodes, because the primary tumor is the one that fails more often than the lymph nodes, and that's compared to PACIFIC in the control arm. PACIFIC-9 is another trial in the same line as the other PACIFIC trials. That one is using dual checkpoint inhibition versus the control arm being PACIFIC. So there are three arms in that trial, durva and oleclumab, durva and monalizumab versus the PACIFIC arm. And that trial is completed accrual, but we have no results from that study yet. Johnson & Johnson has a trial open looking at a nanoparticle. That's a radiosensitizer where bronchoscopy is used to inject the primary tumor and the lymph nodes with a radiosensitizer. That's a randomized phase ll trial that's ongoing. It's got three arms, two different doses of this radiosensitizing drug and then a control arm without injection at all. The control arm is again the PACIFIC arm. And then those of us within the NCI-based clinical trials evaluation program, CTEP, are proposing an intergroup trial that would compare induction chemo-immunotherapy followed by chemoradiation followed by maintenance immunotherapy versus PACIFIC in a phase III study. So I think there's other trials that are either completed, ongoing completed, or on the horizon to assess in this patient population. Dr. Ece Cali: Yeah, we definitely have an unmet need to improve survival outcomes for stage III patients, and it's great to hear that there are so many efforts looking at different strategies to improve outcomes for these patients. Thank you so much, Dr. Bradley, for this informative discussion and for sharing your insights. Any last thoughts? Dr. Jeffrey Bradley: Yeah, we need something, you know. PACIFIC was first reported in 2017, and we really haven't made progress in terms of changing that standard of care control for the last eight years. So we need progress in this area. Dr. Ece Cali: Yep, definitely. Thank you so much for joining, Dr. Bradley. And thank you for listening to . Please come back for more interviews and article summaries and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit . The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. DISCLOSURES Dr. Bradley Honoria: Mevion Medical Systems, Inc. Consulting or Advisory Role: Varian, Inc, Genentech, Inc. Research Funding: Varian Medical Systems Dr. Cali Research Funding Company: BeiGene, Nuvalent, Inc., Astra Zeneca /episode/index/show/jcopodcast/id/39150535

Health Outcomes in Older Childhood Cancer Survivors 11/20/2025

Health Outcomes in Older Childhood Cancer Survivors Guest Dr. Rusha Bhandari and host Dr. Davide Soldato discuss JCO article "Health Outcomes Beyond Age 50 Years in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study, " with a particular focus on mortality data, development of secondary malignancies and the importance of education for both patients and healthcare providers regarding long-term follow-up and care. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Davide Soldato: Hello, and welcome to , the podcast where we sit down with authors from some of the latest articles published in the . I am your host, Dr. Davide Soldato, Medical Oncologist at Ospedale Policlinico San Martino in Genoa, Italy. Today, we are joined by author, Dr. Rusha Bhandari, a Pediatric Hematologist-Oncologist and Assistant Professor in the Department of Pediatrics and Population Science at City of Hope, California. Today, we will be discussing the article titled " ." So, thank you for speaking with us, Dr. Bhandari. Dr. Rusha Bhandari: Thanks so much for having me. Dr. Davide Soldato: So, I just want to go straight ahead in the paper and start from the title. So, we heard that you included in this study childhood survivors of pediatric cancer that were aged 50 years or higher. So, this is a very critical life stage when we know that there are a lot of aging-related comorbidities that can happen, also in the general population but potentially specifically in childhood cancer survivors. So, first of all, I wanted to ask you, why this specific study in this very specific population? Because I think that we had already some data in younger survivors, but now we are focusing specifically on patients aged 50 or more. Dr. Rusha Bhandari: Absolutely. So, to answer that question, I'll take a little bit of a step back in terms of where we are now and where we came from in terms of treatment for childhood cancers. So, thankfully, we now have great curative therapies and survival rates for many childhood cancers, including the most common ones. But this was not necessarily the case 50 or more years ago. So, we essentially are now seeing the first generation of older survivors who are 30, 40, or more years from completion of their cancer treatment. As you pointed out, we know from younger survivors that they have a markedly higher risk of malignancies and health conditions than the general population. You don't typically expect to see things like heart disease or diabetes, for example, in a young adult. But the question that remained was what the health status and risk of these conditions are in survivors who are entering this critical age, as you mentioned, 50 or older, when you do start to see these aging-related changes in the general population. And the question is whether we're still observing increased risks related to cancer treatment that was delivered 30 or more years ago in these survivors who are now entering ages 50 and beyond. Dr. Davide Soldato: Thanks so much. You used the data from a study that is called the Childhood Cancer Survivor Study. So, just a little bit of explanation for our listeners. How is the study conducted? What type of data are you collecting? And specifically for the interest of the study that was reported in this manuscript, which outcomes were really important for you and were so evaluated in the manuscript? Dr. Rusha Bhandari: Yes. So, the Childhood Cancer Survivor Study is a really excellent resource that combines information from children who were treated across North America at various different centers and sites. So it gives us a really good understanding of how different survivors are doing as they do progress through their survivorship journey. The Childhood Cancer Survivor Study includes a baseline questionnaire when participants are first eligible or first enter the study, and then includes a series of follow-up questionnaires to really understand how they're doing, like I mentioned, as they progress throughout their survivorship journey. And so for this study, we really wanted to take a global look at how these patients were doing as they entered that older age range. And so we wanted to look at outcomes ranging from mortality through the health conditions that we've seen from other survivorship studies, including subsequent malignant neoplasms, other health conditions, I mentioned earlier heart disease and other comorbidities we know survivors can be at increased risk for, and also things like frailty, which we know is, you know, the most widely recognized phenotype of aging. And we see that earlier on in our younger survivors. We want to see how this translated to these older survivors and then also other health outcomes like their health status. What is their self-report of their physical health, their mental health? Things like that. So we wanted a very comprehensive understanding of their health. Dr. Davide Soldato: This is a very comprehensive study. Right now it includes more than 30,000 patients that have been treated for childhood cancer, but specifically looking at the question of survivors aged 50 years or higher, you included more than 7,000 patients inside of this study. So, looking at the first outcome that you mentioned, which I think it's also one of the most important, you look specifically at mortality, and in this specific population, you saw a striking three-fold increase in mortality when comparing these survivors with the general population. I just wanted to dive in this result and ask you: What do you see as the main driver for this excess mortality in this population of survivors? And as you were mentioning, the study also collects information about the treatment received. So, was there any association with a specific kind of treatment that was received for curing these childhood cancers? Dr. Rusha Bhandari: I agree. I would say it's striking to see that mortality risk among the survivors relative to the general population. And we do know, again from prior studies, that survivors of childhood cancer do have an increased risk of mortality compared to the general population, but I think looking at those curves of the cumulative mortality risk was really quite striking as they diverge, and that's, you know, just so long past their initial diagnosis and treatment. We know that subsequent malignant neoplasms or secondary cancers are a really an important contributor to mortality among survivors. And I think it was important to note that even in these older survivors, it's still such an important contributor to mortality, and I think this really highlights the need for us to better understand what is driving specific secondary cancers and what are the differences in the biology and treatment approaches for some of these cancers? And how might that then be contributing to the mortality risk? Dr. Davide Soldato: Related to the treatment mortalities - because I think that one of the main forces of the study, as it is conducted, is that it contains a lot of information regarding radiotherapy, allogeneic transplant, surgery, type of chemotherapy received by these survivors - so, are we able right now with the data that we have to pinpoint which of these treatments can potentially lead to such increased risk of mortality? Dr. Rusha Bhandari: So, we weren't able to look at the comprehensive treatment exposures and mortality risk for this paper. So that might be one of the questions I would put on the side. We were able to look at that in relation to subsequent malignant neoplasms and health conditions though, as you mentioned. Dr. Davide Soldato: Another thing that I think is very important is that you were able to look at specific causes for mortality. So for example, you mentioned the increased rate of neoplasm in this population and specifically, more or less 7.6% of the patients that were included in the study developed another neoplasm after the ones they were cured for in the childhood period. So, you saw a wide range of cancer, for example, bone and soft tissue sarcomas, breast cancer, genitourinary cancer. And as you were mentioning, there were some associations for treatment modalities that were associated with a higher risk of developing this type of cancer. Can you expand a little bit on this? Dr. Rusha Bhandari: Absolutely. And so the key part here was that we really looked at any of these outcomes that occurred beyond age 50. What we found was there is still an increased risk of secondary cancers beyond that initial childhood cancer diagnosis, but when we really looked at that data, it was specifically among survivors who had a history of receiving radiation. And we did not necessarily see an association between different chemotherapy exposures and secondary cancers. And I think this speaks to what we're now learning in terms of the very long-term effects of radiation and how that impacts ongoing health risk even in patients who are 30 or more years out from their treatment. And I think it really highlights the importance of these- the efforts that have been made in the more recent decades to really try and reduce or eliminate radiation where possible, you know, as we've come to understand more about these long-term effects from it. Dr. Davide Soldato: A clear association with radiation therapy but no association when we look at specific types of chemotherapy that were used for curing this childhood cancer. Another thing that I think it's very interesting and you briefly mentioned before is that potentially when we look at these secondary malignant neoplasm that develop in this situation, we might also see some outcomes that are not comparable to the one of the general population, meaning that we managed to cure less this type of cancer when they develop in these childhood survivors. So, I just wanted to understand if you could provide us with a little bit of perspective also from a clinical standpoint being a pediatric hematologist-oncologist as to why this might be happening and how can we potentially increase the cure rate also in this population of childhood cancer survivors? Dr. Rusha Bhandari: Absolutely. While that was not the focus of this study, it was something that we were certainly interested in is understanding how even once a childhood cancer survivor, for example, develops a health condition or a secondary cancer further into survivorship, how does that outcome then differ from someone in the general population? And there's a lot of interest in ongoing studies actually evaluating that and understanding what are the differences from the initial presentation, biology, the characteristics of that cancer, through how they're treated. So I don't know if we have all of the answers for that quite yet, but you can imagine if someone hypothetically had a history of receiving a lot of anthracycline chemotherapy or already having received a lot of radiation, that might impact what treatment they might receive for that secondary cancer or if they already have other existing comorbidities that need to be taken into consideration. Dr. Davide Soldato: Speaking about comorbidities, you were mentioning in the beginning that one of the focuses of this scientific work was really to try and see whether also this type of adverse health outcomes that can be potentially related to treatments were more frequent among these childhood cancer survivors. So I think that it's very interesting that for this comparison, you were able to use the data from the siblings of the patients who were included inside of the study. So, just a little bit of a comment on why you decided to use this specific methodology, which I think has a very nice touch to it when we look at these outcomes like, for example, diabetes or cardiovascular disease, and in general, do we see an increased number of chronic health conditions among survivors who were treated for childhood cancers? Dr. Rusha Bhandari: Yes, so this is a really excellent strength of the Childhood Cancer Survivor Study is that they have information, longitudinal information, on survivors as well as their siblings. So, you know, when we were discussing the design of the study, I mentioned that we have initial baseline questionnaires as well as multiple follow-up questionnaires, and that is for both the survivors and the siblings. And so we're able to really understand their health course over time. We chose to evaluate sibling data because then you're really able to look at people who have similar characteristics, right? Similar environmental exposures in theory, potentially similar genetic predispositions and makeups and things like that. And so you can really try and have as good of a comparison as possible. Dr. Davide Soldato: Did we see any increase in chronic health condition when looking at survivors compared to the siblings? Dr. Rusha Bhandari: We did. And while that's been reported before, again, I think it's important to demonstrate that in this older population when you would expect that these siblings would now also be starting to develop different health conditions. Dr. Davide Soldato: One thing that was very interesting is that when we look at the coexistence of multiple comorbid conditions and chronic condition in this population, we also see that for some of these survivors, they basically have the same rates of comorbidities as compared to siblings who are potentially 20 years older than them. So I think that there is really that striking point, as you were mentioning before, of accumulation of changes, also physiological changes that can potentially drive a higher frailty index, which was also higher when looking at these survivors compared to their siblings. One outcome that was really not that worse when we look at survivors of childhood cancer was actually mental health. And as I read the paper, it was something that really surprised me a little bit because you would imagine that going through such a harsh diagnosis, such very complex treatment, very early in their life could potentially lead to some worse health outcomes also in terms of mental health over time. But this was not seen. And just a comment on this, because I think it's a very surprising data. Dr. Rusha Bhandari: Yes, I appreciate that question. So, as you mentioned, mental health is such an important issue for patients, both those undergoing treatment as well as those in long-term survivorship. And in our study, we found that survivors were not more likely, as you mentioned, to report poor mental health compared to their siblings. And I think there's a few possible reasons for this. You know, again, this is self-reported data amongst siblings and survivors who survived to at least 50 years of age and completed a questionnaire. And so that is the group of individuals that we were able to evaluate this in, so we have to keep that in mind. But I think our findings may also reflect the resilience of this particular cohort of aging survivors that we included. This finding has been reported in other studies of survivors as well, and so I think it very well may speak to the resilience of the cohort that we're looking at. Dr. Davide Soldato: Going back just a little bit, you mentioned that the majority potentially of these survivors who were included in the current analysis were treated between 1970s and 1980s. So, as you were mentioning before, radiotherapy was seen as a significant contributor to second neoplasm and also to the increase of this chronic health condition. So, do you believe that there is still a role for these survivorship studies as we are approaching treatment modalities where radiotherapy is administered less frequently or with lower doses or omitted at all in the treatment course of these survivors? Dr. Rusha Bhandari: Absolutely. I think you mentioned a very important point, which is these findings are most applicable to the patients who were included in this cohort or similar cohorts, those who were treated in the 1970s and 80s who now are 50 years or older at this point in time. And as you know, treatment modalities have really changed. You know, as you mentioned, we'll use less radiation in many cases whenever possible, but there are so many new modalities, so many different chemotherapeutic agents, immunotherapy. There's so much more we need to learn about the long-term effects of some of these newer treatment modalities. And also, we've been able to really intensify our treatment regimens with improvements in both treatment approaches and supportive care. And so I think we have a lot to learn about those late effects, and ongoing studies are certainly needed as we continue to have this growing population of older survivors. Dr. Davide Soldato: And now a more general question which builds on the results of the study but goes a little bit beyond what was the scope of the research. So we have just discussed that there is an excess mortality in general, there is a higher risk for secondary malignancies in this population, we see higher accumulation of chronic comorbid conditions that need to be treated. So building on these results, in your opinion, what would be the best framework to follow up these patients over time? Because I imagine that for some of these patients who have been treated 30, 40 years before the moment where we see this type of events, they can be potentially also discharged from more specialistic medical care. So what is the best course of action? Should we keep all of these patients under observation in a very specialistic environment under the care of the oncologist or the pediatric oncologist? Should we create a stronger bond with general practitioners so they know that there is this problem? Dr. Rusha Bhandari: Yes, I mean, I think you're reading my mind. We thankfully do have evidence-based guidelines. We utilize the Children's Oncology Group Long-Term Follow-Up Guidelines, which include screening recommendations for secondary cancers, chronic health conditions, everything based on the underlying diagnosis and treatment that these patients received. But we recognize that a large proportion of these survivors do not continue to have lifelong follow-up at a survivorship center, but really do need that specialized screening based on their treatment that they received. And I think for that reason, it's so important that we continue to build relationships with their primary care providers and really make sure that both patients and their providers have this information at hand regarding what their treatment is and what the screening is that they need and that we be able to have this community whereby we are able to help inform the screening in our own survivorship clinics, but also help guide some of the primary care providers who are going to be seeing these patients in the long run. Dr. Davide Soldato: Do we have any data showing what is the adherence rate of these patients to this type of continuous screening and monitoring over time? Because I imagine that that might also be a point for improvement in terms of quality of care. Can we retain as much childhood cancer survivors as we want as we are learning that there are all these potential negative health outcomes over time? Dr. Rusha Bhandari: We definitely within the survivorship community do want to help make sure as many survivors as possible are being engaged, again, whether it's at their specific cancer center or whether it's in the community, recognizing that for many reasons, it's not feasible to always return to that cancer center for your regular survivorship care. I think there's a lot we can do. Going a little bit outside the scope of your question, but I think there's a lot that we can do nowadays in terms of telehealth and being able to communicate with patients and their providers even if they're geographically not located right near us. But we do have data that shows that the further out many... /episode/index/show/jcopodcast/id/39101370

Long-Term Remission After Cilta-cel in Patients With RRMM 11/13/2025

Long-Term Remission After Cilta-cel in Patients With RRMM Guest Dr. Sundar Jagannath and host Dr. Davide Soldato discuss JCO article "," and the efficacy of CAR-T cell therapy in patients with heavily pretreated RRMM (relapsed/refractory multiple myeloma). TRANSCRIPT Dr. Davide Soldato: Hello and welcome to , the podcast where we sit down with authors from some of the latest articles published in . I am your host, Dr. Davide Soldato, medical oncologist at Ospedale San Martino in Genoa, Italy. Today, we are joined by author, Professor Sundar Jagannath, Professor of Medicine at the Icahn School of Medicine at Mount Sinai and the Tisch Cancer Institute. He also serves as Network Director for the Center of Excellence for Multiple Myeloma, and he is an internationally recognized expert in the field of multiple myeloma. Today, we will be discussing the article titled, "." Thank you for speaking with us, Professor Jagannath. Dr. Sundar Jagannath: Thank you for having me, Dr. Davide Soldato. It is a pleasure to be here. is a highly recognized journal among the oncologists, so I am very happy and privileged to be here today. Dr. Davide Soldato: Thank you so much for being with us. So, I wanted to start a little bit with the rationale of the study and the population that was included in the study. So, the trial that we are discussing, CARTITUDE-1, was already published before, and we observed very good results with a single infusion of cilta-cel. So we had previously reported a median progression-free survival of 30 months, and median overall survival was not reached. So, I just wanted to ask you if you could guide us a little bit into the population that was included in the study and also explain a little bit to our listeners what is the drug that we are discussing, cilta-cel. Dr. Sundar Jagannath: It is a CAR T-cell. This is a patient's own lymphocytes, which goes through apheresis and is sent to the company, where they modify it and introduce the B cell receptor. In this case, you know, there is a heavy chain gene receptor for the BCMA, and in cilta-cel, there are actually two receptor sites on each molecule, or there are two binding domains on each receptor molecule. So, it is considered to be quite efficacious. As you reported, the earlier results that the patients who participated, 97% of the patient responded. Now, you asked about the patients who participated in the clinical trial. This clinical trial was conducted between July of 2018 and October of 2019. At that time, this was a phase 1b/phase 2 trial, and the whole idea was to take patients who had relapsed all the available treatment regimen so that these patients were considered to have, in the unmet medical need situation. So, what does that entail? That means the patient should have been exposed to a proteasome inhibitor, to an immunomodulatory molecule, and to an anti-CD38 monoclonal antibody and should have received at least three or more prior lines of therapy and should be actually progressing on their last line of therapy. So with that requirement, if you look at it, the median number of prior therapy on the patients who participated was actually six. So patients were heavily pretreated. They had exhausted all available treatment options. So, they can participate in this clinical trial. And if not, there have been real-world evidence, such as LocoMMotion, which had reported what is the outcome for such a patient if they were treated outside of this clinical trial, if they were treated with the then available regimen. Their median progression free survival would have been only 3 months, and most patients would have lost their life within a year. So, this was truly an unmet medical need with patients in a very difficult clinical situation. Let’s put it that way. So, those were the patients who participated in this particular trial. Dr. Davide Soldato: Thank you very much. And as we mentioned before, the results that were obtained in this clinical trial were really very interesting. And now, in this issue of the , you are reporting data with a longer follow up. So we are actually at more than 5 years of follow up for the patients included in this trial. So, I just wanted a little bit of insight into why you decided to report these long-term outcomes and what type of information do you think you could provide with this study to the medical community? Dr. Sundar Jagannath: This is very important because this was a clinical trial that was done in patients who were, as I said, in unmet medical need. Most of the patients had prior stem cell transplantation, had gone through a proteasome inhibitor. Many of them have had both Velcade and carfilzomib treatment. Most of them had been exposed to lenalidomide and pomalidomide. And as required, all of the patients had to have had prior exposure to anti-CD38 monoclonal antibody or daratumumab. So, the patients were heavily pretreated. Typically, TIL CAR T-cells came into the field at this particular moment, until then, we were developing small molecules, and they usually would have a PFS of 3 months and median life expectancy of a year, the overall response rate of 30%, and that is how, if you look back, that is how carfilzomib was approved, that is how pomalidomide was approved. So, the drugs which were approved, including daratumumab, you know, the response rate was in the same ballpark. So you would see that most agents, single agents, would have had a response rate in the neighborhood of 30%, the progression-free survival would have been between 3 to 5 months or 6 months at the most, and the life expectancy was short. And here comes a drug, and when I was following the patients at Mount Sinai, I found that there were a subset of patients, they got one-time treatment and they were in complete remission, no trace of cancer with annual evaluation with PET CT and bone marrow evaluation for MRD. So, I said this is remarkable, and this needs to be reported. And I went to the Janssen and company, and they agreed to review the entire experience. This is remarkable that 32 of the 97 patients, or one third of the patients, were alive and progression-free. This is unheard of for any clinical trial until now, that the patient will be progression-free, one third of the patients on a clinical trial will be progression-free, in the late stage of their disease. So that is the most important impact. And that is why this 5-year follow-up results were presented. Dr. Davide Soldato: Thank you very much. That was very clear. And as you said, we are speaking about a population that was heavily pretreated, that had exhausted all type of treatment options outside of a clinical trial. And as you said, one third of the patients was alive and progression-free after 5 years from being included and infused inside of the study. So, considering this population that, as we said, had received all treatment options, I was wondering if you observed any kind of differences in terms of disease characteristics when looking at these patients that had exceptional response, so, alive and progression-free at 5 years, and the patients that sadly had developed a progression after the infusion in the study. Dr. Sundar Jagannath: This is very important because we wanted to see who are the patients who are having this exceptional outcome. And we looked at all the 97 patients. If we look at all the patients, we saw that there were initially, out of the 97, 17 patients died earlier in the disease course due to treatment related complications, etc. But there were about 46 patients who had progression of disease and 32 patients, or one third, were alive without progression of disease. Then we looked at the 46 patients who had progression of disease. Of them, we found that 30 had disease progression and its complication, and there were actually 13 patients who were still alive even after progression of disease. So we decided to compare these 46 patients who had progression of disease versus 32 patients who had no progression of disease to see what is the difference. To our surprise, the age was similar, male, female distribution was similar. High-risk cytogenetics, which we would have thought, you know, that is why we say high-risk disease, the term, high-risk cytogenetics was equally distributed. That was really a surprise. Number of lines of prior therapy, number of exposure to drugs, all of that was the same. So that was also interesting. But a theme did emerge. Patients, in general, tend to have lower burden of disease who had the exceptional outcome. But there is one which we considered as bad, the extramedullary disease. Multiple myeloma being a blood cancer, it is usually in the bone marrow. When it starts growing outside of the bone marrow, the extramedullary disease, usually it portends poor prognosis. But we were surprised that actually there were an equal number of extramedullary disease patients even in the long-term survivor as those who had progressed of disease. So the most important takeaway was patients who had lower burden of disease, they had less number of myeloma cells in their bone marrow, percentage wise, and the soluble BCMA level was lower. Soluble BCMA is an indirect measure of the amount of plasma cells in the patient's body. It is like a tumor burden. So they were low. So, this was an important finding because it has future ramification, as you can understand. If this treatment is made available earlier in the disease course of the patients, where we are able to control the disease better, then more patients are likely to have such wonderful outcomes as one third of the patient experience in the late stage of the disease. Dr. Davide Soldato: So, you already mentioned soluble BCMA as a marker of potentially better prognosis as being correlated to a lower volume of disease. I was wondering if you could give us some more information about the biomarkers that you evaluated in the study. For example, you evaluated a little bit the CAR T expansion kinetics and also some others that I think could be interesting and could point to some population that experienced such important benefit. Dr. Sundar Jagannath: That is a very important point because CAR T-cell, it is a live cell and its efficacy depends upon how well the CAR T-cell is going to function. And then, you know, the patient undergoes apheresis. This is a patient's own lymphocyte. So first and foremost is who would generate good CAR T-cell. Those who have plenty of lymphocytes at the time they are coming for apheresis. This is likely to happen earlier in the course of the disease than in patients who have gone through numerous lines of therapy and exhausted. So, in this particular trial, of course this was in late stage of the disease, and so we were able to show patients who had lower number of T cell in circulation, and the way to measure is if they had more neutrophils and less lymphocytes. So that is what is called as a higher T cell over neutrophil, they did better. If they have more neutrophil than T cells, then they did not do well. So, procurement. The second one is also whether the T cells are more naive, you know, not exhausted T cells. So more naive T cells, if you are able to procure from the patient, they did very well. Now, after the CAR T-cell manufacture, then the expansion, when you put it back into the patient, if the T cells expand very well, so that the effector, that is the CAR T-cells to the tumor ratio is good, so there are more effector cells, the CAR T was able to expand and the amount of tumor was less, then the efficacy was very, very good. As I said, the patients in this group, those who had a lower burden of disease, they did better, and that is because of the CAR T-cell expansion, so the effector to the target ratio was favorable. So that is another important. And then there are also the type of CAR T-cells, having CD4 T cells with central memory phenotype at the peak expansion also makes a difference. So all of that matters. But this is important because the efficacy of the CAR T-cell, it is persistent, long persistent and keeping the cancer down. Its ability to get rid of the cancer completely at the first go around because usually we are not able to detect the CAR T-cells beyond 6 months in the majority of patients and very rarely after a year or two. So it is very uncommon to find the CAR T-cells in circulation or even in the regular bone marrow evaluation. So, efficacy, the expansion, having naive T cells, having good effector to target ratio and more central memory kind of T cell, because if it is all effector T cell, they will get quickly utilized and get exhausted, whereas the central memory cells can expand more and give more effective CAR T-cells. Dr. Davide Soldato: Thank you very much. I was wondering if you could guide us a little bit into what is your opinion regarding the positioning of CAR T-cells given all of these logistics that is necessary compared, for example, with bispecific antibodies against BCMA, which have the same target, but they do not have all of these logistics before being administered to the patient. Dr. Sundar Jagannath: That is a very important question, how to sequence these treatments now that we have two BCMA-directed CAR T-cells available. We have three BCMA-directed bispecific and one GPRC5D-directed bispecific antibodies are available. And so the question comes in for at least the currently approved CAR T-cell therapy, there is an obligatory time. You have to go through apheresis and you have to ship to the company, and there is a manufacturing time, roughly about 2 months before they can receive it. During that time, you want to make sure the patient's disease is under control. So that is a given. There are several ways to look at it when we evaluate the patient and talk to the patient. One good thing is now the two CAR T-cells which are approved, one is cilta-cel we talked about, and the other one is ide-cel. Ide-cel is approved in earlier line of therapy, two or more prior lines of therapy, and cilta-cel is approved in patients who have failed one line of therapy and who are lenalidomide refractory. So, the treatment of CAR T-cell is available earlier. And as I said, when you administer CAR T-cell earlier, you are able to keep the disease burden down, and it is a one and done deal. There is a better quality of life for the patient, and you are able to produce long, durable remission and potentially a cure. Now coming to the bispecific, they are currently available in later lines of therapy. So if you look at it from a patient's perspective, you can use the CAR T-cell earlier and then go through the bispecific therapy. But if the patient comes with relapsed refractory myeloma and has not used the CAR T-cell therapy and has not used the bispecific therapy, then the physicians have to decide which one they want to use. If somebody's disease is rapidly progressing and they need immediate tumor reduction and they have already exhausted all available therapy, then going through BCMA bispecific therapy is quite appropriate. And secondly, CAR T-cell therapy is generally given to somewhat physically more fit patients, whereas bispecific therapy, because you are giving antibody at step-wise dosing in this patient, and you have the ability to stop at any particular dose and then come back and redose, whereas CAR T is, you just give it to them one time, you have a lot more control. So intermediate frail or even frail patients can go through bispecific therapy, whereas it would not be in the best interest of the patient to go through a CAR T-cell therapy when they are frail. So that is another important point. But from the information available, when the patient goes on a BCMA bispecific therapy and they start progressing on treatment, usually it is their T cells are exhausted or the BCMA is no longer expressed on the tumor cells. So coming with CAR T-cell later on is usually not effective, whereas giving CAR T-cell earlier, if the patient relapses later, they have good T-cell function and most of the time the BCMA is still expressed. So you are able to give the BCMA to the maximum benefit by using the CAR T first and BCMA later. So if somebody asked me how to sequence this, just off the bat, you will say CAR T first, BCMA bispecific second. But as I said, there are unique situations. Then there is another potential that is happening. You can change the target. You can use a BCMA against GPRC5D to reduce the tumor, and then go ahead and consolidate it with a CAR T-cell therapy. That is also possible. You are changing the target from GPRC5D to BCMA, the tumor is already down, so the patient is likely to benefit. So these are all newer treatment options which have become available to the physician. So they will have to look at individual patients and decide what is the best course of action for that patient. Dr. Davide Soldato: So, I just wanted to close a little bit with your opinion about how these results translate into clinical practice. So considering this outstanding 5-year data that we have seen, one third of the patients who are alive and progression-free after a single infusion of cilta-cel, do you think that we could start to think about functional cure even in patients who have a diagnosis of relapsed refractory multiple myeloma? Dr. Sundar Jagannath: My feeling is this is important because in this particular study which is published, 12 patients who were followed at Mount Sinai out of the 32 patients who are alive and progression-free, 12 were followed at Mount Sinai. And they were evaluated every year with bone marrow MRD testing by clonoSEQ in 11 of the 12 patients, and one was by multiparametric flow cytometry. So most of them were 10 to the minus 6, not even one in a million cancer cells, and all of them had functional imaging, which is called PET CT every year. So these were patients who had no evidence of disease that we could detect with the technology available today, serologically, in the bone marrow, or anywhere else in the body with a PET CT. They were found to be disease free after a single infusion of cilta-cel. So, that would be almost to the definition of a cure because if you look at cure as a definition for any cancer, cure is defined as a state of complete remission with no trace of cancer that persists over a period of 5 years or longer without maintenance. And that will be applicable for breast cancer, lymphoma, leukemia. So it is a general statement. And if we use that in myeloma too, then I could say that these 12 patients from my center, we proved that they are cured of their myeloma. They are not functionally cured. You’ve got to remember, there is only cure. That was the definition across all diseases. So there is nothing like a functional cure. They are cured of myeloma. So is myeloma curable? This is the first time we are looking at that. We do know, every physician treating myeloma that there are patients out there, 10 year and beyond, without evidence of disease. This has been published by University of Arkansas, Bart Barlogie's group, who has been saying that myeloma is a curable disease for a long time. And many others have shown long-term follow up. But this one in a late stage disease, we were able to show that they were one treatment with no maintenance. All other studies have been in newly diagnosed myeloma patients. Nobody has shown in late relapse patients on a clinical trial a third of the patient will be progression-free. And 12 of them who were studied were actually disease free. So they were cured of the disease. So if we accept that, then the next question is, first step towards cure is achieving complete remission. They should have no monoclonal protein by any technology you want to use, no measurable residual disease using next gen sequencing or clonoSEQ, and functional imaging whole body PET CT or whole body MRI. So that is important, definition of the complete remission. And... /episode/index/show/jcopodcast/id/38744685

JCO Article Insights: Xevinapant Plus Chemoradiotherapy in Unresected LA SCCHN 10/27/2025

Income Among Adolescents and Young Adults Surviving Cancer 10/09/2025

Income Among Adolescents and Young Adults Surviving Cancer Host Dr. Shannon Westin and guest Dr. Giancarlo Di Guiseppe discuss the JCO article "" TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hi everybody and welcome to another episode of , the podcast where we go in depth on manuscripts that are published in the . I'm your host, Dr. Shannon Westin, social media editor of and gynecologic oncologist extraordinaire. I'm so very excited to talk to you today. We're going to speak about "." And I'm joined today by Dr. Giancarlo Di Giuseppe. He has a PhD in epidemiology that he actually just defended with this very work you're going to hear about today at the Dalla Lana School of Public Health at the University of Toronto. He is now a research fellow at the Hospital for Sick Children. Welcome, Dr. Di Giuseppe. It's so exciting to have you. Dr. Di Giuseppe: Thank you so much for having me. Dr. Shannon Westin: So we'll get right to it. Let's level set. Can you talk a little bit about the financial impact of cancer on survivors in general? I think this has been a growing area of interest and research, certainly. Dr. Di Giuseppe: Yeah, and I think that's a very important question, and I'm so happy that this research is now becoming more popular in the research world because it really addresses a critical issue that cancer survivors and their families must face. You know, you're diagnosed with cancer, and now you need to take time off work because you're hospitalized for chemotherapy. You're going back and forth to the hospital, and that all requires time away from your employment, and as a result of that, that has a significant financial strain, both on you and your family. And that's during therapy. Now, in survivorship, in the years after you've survived your cancer, you still need to deal with all the late effects associated with your treatment and your disease, and that can be psychological, physical, and that impacts your workability as well. So, it's not just exclusive to individuals undergoing treatment but also in survivorship afterwards. It really gets the financial strait that you face as a cancer survivor because you're time away from work and your lost productivity. Dr. Shannon Westin: Yeah, that makes sense. Then I think it would be great to talk a little bit specifically about the patient population that you studied in this particular manuscript. Can you talk a little bit about the adolescent young adult cohort, you know, why you singled out this particular group of people? Dr. Di Giuseppe: Absolutely. Adolescents and young adults, or AYAs, which I'll now refer to them as - I'm one of them - we're at a unique crossroads of our life and in our developmental stage of life. We are finishing our post-secondary education. We're entering the workforce. We're forming romantic relationships, and we're really achieving financial autonomy. It's because of this unique developmental stage in life where we've become quite susceptible to health shocks such as cancer. Really, does a cancer and the associated negative financial impacts affect our long term trajectory? So, I'm just finishing my PhD. If I was diagnosed with cancer, I would require a year or two away from my studies. I may or may not finish my education that could then impact my employment and then my financial outcomes later on in life. So it's really this unique population who are going through so many transitions and changes in their lives. How does that cancer really impact that life course trajectory? I think it's unique from an adult who might have, you know, large savings where they can bear the brunt of their cancer financial impacts, whereas AYAs may not have that same financial stability, provide a safety net for the financial impact resulting from their disease. Dr. Shannon Westin: You broke my heart a little bit. I realized I'm no longer in that group, so I guess it's time to move on. Okay. So, let's talk a little bit about the overall design of the study. Can you just kind of walk us through how you set everything up? Dr. Di Giuseppe: Yeah, absolutely. So it's a matched cohort study at the population level here in Canada. We have large national administrative databases, and we have this really unique set of data at the national level through Statistics Canada that we can link our cancer registry to tax records. It really provides this unique opportunity to longitudinally follow individuals from their disease forward in time. The main overall design is the matched cohort study. At the time of diagnosis of a cancer case, they're matched to someone from the population on certain characteristics. I follow these individuals from the index date of their cancer case forward in time. The crux of the study itself is a quasi-experimental two-group pre-post study design where I have information before the cancer diagnosis, I have information from their income after their cancer diagnosis, and it's really quantifying how much does that total income change from before the cancer to the after-cancer period. Dr. Shannon Westin: I'm always intrigued about hearing more about financial toxicity in general, certainly very multi-dimensional. Can you speak a little bit about the different ways that you can assess this and measure this and kind of what you chose? Dr. Di Giuseppe: Yeah, so financial toxicity really has two main spheres of measurement. There's a direct and the indirect measurements of financial toxicity. So your direct financial toxicities could be related to actually paying for medical treatment and any sort of financial burden as a direct consequence of your disease. Fortunately here in Canada, we have a universal health care system, so patients don't have to pay directly for most of their treatment. There's also indirect financial toxicities, which are not a direct result of the disease. So in this study here, one of the, or the indirect financial toxicity that I measured was the financial impact to income. That's not the only indirect financial toxicity. There could be out-of-pocket expenses for drugs that may not be covered in the universal health care system here. It could be lost productivity at work. There's really this direct and indirect financial toxicities that together result in a significant financial burden and hardships for cancer patients and survivors. Dr. Shannon Westin: Okay, so you guys did a lot of matching. It was extensive. Can you speak a little bit about the factors you used to match your patients and your controls and kind of why you chose them? Dr. Di Giuseppe: Yeah, absolutely. The matching I think is a really critical aspect of the study, and it really establishes this baseline period of individuals who are cancer-free, who look as similar as possible to the individuals who would eventually develop cancer. So I matched on birth year, sex, marital status, whether or not they had children, if they were born here in Canada or not, as well as a geographic measurement of census division. So it's really in the city or in a rural town. Then I also matched on a 5% buffer of their total income in the year prior to the cancer diagnosis. All this matching was really done in the year before they were diagnosed, and it's to establish this comparator cohort of individuals from the general population who looked as similar as possible to the individuals, or the AYAs, who would develop cancer. It's again to establish this baseline period of a control cohort who looks as similar as possible. So any differences that we might see after the cancer can be attributed to the effects of the AYA who would develop cancer. It's quite powerful, I think, from a study design perspective because it establishes causal inference methods through the study design and through the matching itself. Fortunately, I was able to match on an extensive list of covariates given the large population-based data that I used, particularly the tax records. Tax records contain a whole wealth of information, your marital status, your sex, your income, where you live. So it really provided this rich opportunity to match as closely as possible the AYAs who would develop cancer to someone from the population who wouldn't. Dr. Shannon Westin: Yeah, and I mean I think that's the only way to do this type of research and really make it generalizable and actually, you know, know that you can trust the results that you've got. So I just want to again congratulate you because I think this was just- when I read the design, I was so impressed. So now that we know the design and we understand everything, let's talk a little bit about the characteristics of the actual patient population that you studied. Dr. Di Giuseppe: Yeah, for sure. So average age of diagnosis was in their early 30s, so around 32 years old. The breakdown of the population was mostly females, so I think two-thirds of the cohort were actually females who were diagnosed with cancer. Really, a lot of the cancers were thyroid and the breast cancers. These cancers are more common in women than they are in men. So it's really reflective of the different distribution of cancer in AYAs compared to other populations like in children or in older adults. Dr. Shannon Westin: All right, bottom line. What did your primary analysis demonstrate and how was the income different based on the types of cancer that people might have been diagnosed with? Dr. Di Giuseppe: Yeah, the bottom line is actually quite a disturbing message, I would say, and it's really that cancer causes this long, prolonged financial hardship in survivors. That's, I think, a very important result from the study, and I think it has far-reaching implications. This study demonstrates that these individuals who were diagnosed with this disease that is unforeseen also pay a financial price, and that sustains for many years after their diagnosis. That's overall on average. Once I dove deeper, actually looking at the different cancer types, the message actually gets even more disturbing, I would say, particularly in some disease subgroups. So the central nervous system cancer survivors really have a large reduction in their income, which sustains over 25%, 10 years after their diagnosis, and they never really recover financially from their disease. There are some groups of cancer survivors who really pay a large financial price for their disease. Dr. Shannon Westin: I don't know if you're able to tease this out. This is just me thinking off the top of my head. Do you think it's the long-lasting side effects? Dr. Di Giuseppe: I think you hit the nail on the head there, absolutely. I think what we're seeing here is a direct result of the late effects that cancer survivors experience. CNS cancer survivors, whether that is a surgical resection, radiation to the head for their tumor, the late effects really impact these individuals in the post-cancer survivorship period. So I think what we're really seeing are these late effects here. Dr. Shannon Westin: The other thing I was kind of struck by is the differential and income loss over time. Can you speak a little bit about that in your work? Dr. Di Giuseppe: Yeah, absolutely. There really is this period of financial vulnerability in the first couple years of diagnosis. So that's year zero, one, two, and three, these first couple years when these individuals are diagnosed with cancer, they are significantly impacted by their disease financially. Some of these reductions in their income is 15%, 20% in the year of diagnosis and the year afterwards. It's unsurprising because this is when these individuals typically are undergoing their treatment. They're not working. They may have even lost their job or quit their job. So it's really reflective in the results in that first few years of their diagnoses where these financial impacts are the largest. I think it provides an opportunity where certain interventions might alleviate some of these large reductions in their income. Dr. Shannon Westin: Well, I really was disturbed by your work, and I hate to kind of say it that way because it's such important work. So I'm really- congratulations on everything that you're able to achieve and especially your PhD. But I think shining a light on these types of things is always pretty rough when you really look at the nitty-gritty details. So any thoughts about where we go from here, how do we support these people? Dr. Di Giuseppe: I think we can support them at multiple different levels. So at the individual level, I think within the clinic setting, financial screening for financial toxicity, financial literacy, I think all these things can be incorporated into cancer care continuum to kind of educate AYAs with cancer about the financial implications of their disease, both in the short and the long term. So I think educating these cancer patients is important. I think at the employer level, really working at the institutional level to incorporate workplace accommodations that might facilitate the return to work process for cancer survivors after their treatment or during, I think would also make the financial burden slightly less if cancer survivors are able to return to work or not have to quit their job because of their disease. And then return to work easier, I think might alleviate some of the employment consequences that these individuals face, which then lead to their adverse financial effects. Then I think also at the policy level, at the governmental level, whether that's incorporating any sort of fiscal stimulus for cancer survivors, whether they're under treatment or in survivorship, any sort of tax breaks that they might be available to them to kind of alleviate some of that financial stress. The reality of it is being diagnosed with cancer and having your income reduced by even 5% - cost of living is expensive, especially now - so I can't even imagine what cancer survivors who are in this economy are facing with rising inflation and cost of living going up. So I think really having tax breaks as well as financial aid for these cancer survivors could really support them both in their cancer journey while they're undergoing treatment as well as some of the sustained effects that they experience afterwards. It's particularly important, as we touched on earlier, for CNS cancer survivors, right? These individuals have this sustained effect that never really returns back to normal, and I think having sort of disability pension or kind of financial aid for these individuals to support them, I think is important. Dr. Shannon Westin: We see this all the time in gynecologic cancers, these young women that support their families, young children, and then lose their ability to do so due to their diagnosis and the treatment they have to receive. So I can't say this enough how important this work was and how honored I am to get to speak with you today. I learned a ton. And thank you to all of you listeners. We're just so excited to have you. This has been long term dynamic financial impacts among adolescents and young adults with cancer: a longitudinal matched cohort study. Thanks again for listening to , and please do wherever you get your podcasts. Have an awesome day. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. /episode/index/show/jcopodcast/id/38357215

JCO Article Insights: Phase I DLL3/CD3 T-Cell Engager in DLL3-Positive SCLC or NECs 09/29/2025

JCO Article Insights: Phase I DLL3/CD3 T-Cell Engager in DLL3-Positive SCLC or NECs In this JCO Article Insights episode, Dr. Ece Cal interviews Dr. Martin Wermke, author of the JCO article, "." TRANSCRIPT The disclosures for guests on this podcast can be found in the transcript. Dr. Ece Cali: Welcome to this episode of . This is Dr. Ece Cali, editorial fellow, and today I am joined by Dr. Martin Wermke, Professor for Experimental Cancer Therapy at Dresden University of Technology, to discuss the manuscript “.” Obrixtamig is a bispecific T-cell engager that binds to DLL3 on tumor cells and CD3 on T-cells. This manuscript presents the phase 1A dose escalation results of Obrixtamig in patients with DLL3+ small cell lung cancer and neuroendocrine carcinomas. In this study, 168 patients were treated with Obrixtamig across four different dosing regimens. 49% of the patients had small cell lung cancer, 42% had extrapulmonary neuroendocrine carcinoma, and 8% had large cell neuroendocrine carcinoma of the lung. Patients received a median of two prior lines of therapy. 33% of the patients had brain metastases at baseline. Of note, this trial did not mandate baseline brain imaging. Maximum tolerated dose was not reached. 88% of the patients experienced a treatment-related adverse event, however, only 3.6% of the patients had to discontinue treatment due to treatment-related AEs, and dose reduction due to treatment-related AEs was documented in 2.4% of the patient population. Similar to the other DLL3-targeted bi-therapies, the most common adverse events included CRS in 57%, dysgeusia in 23%, and pyrexia in 21% of the patients. CRS events were mostly mild. They occurred more frequently in the first two to three doses. 9% of the patients experienced ICANS, of which 3% were graded as Grade 3 or higher. And let's review the efficacy results. Responses were only seen in patients who received 90 microgram per kg or more once weekly or once every three weeks dosing. The objective response rate in patients who received an effective dose was 28%. If we review by tumor type, 21% of the small cell lung cancer patients, 27% of the extrapulmonary neuroendocrine carcinoma patients, and 70% of the large cell neuroendocrine carcinoma patients had objective response. Median duration of response was 8.5 months, though this data is immature due to short follow-up. Dr. Wermke, DLL3-targeted bispecific T-cell engagers are reshaping the treatment landscape of small cell lung cancer. This trial investigates Obrixtamig in other high-grade neuroendocrine tumors as well. Can you put this trial into context for us and explain why it may represent an important step forward? Dr. Martin Wermke: Yeah, thank you for providing me with the opportunity to discuss our data today. I think the data with Obrixtamig in small cell lung cancer are largely similar to what has been observed with other bispecific T-cell engagers such as tarlatamab with respect to the response rate and duration. It has, however, been to be mentioned that BI 1438001 had a bit more liberal inclusion criteria than other trials around. You already mentioned the fact that we allowed the inclusion of patients without mandatory brain imaging, which led to some patients having their brain mets been diagnosed during the treatment with obrixtamig and then adding to the progressive disease patients. That is something which was not the case with the tarlatamab trials where you really had to have a brain imaging before, and in the Phase 1 trial you were even required to treat the brain mets before you included the patient. So it is a bit different, more poorest patient population. I think the trial adds on existing data by being the first trial to also include non-SCLC neuroendocrine carcinoma of other origin, for example from the gastrointestinal tract, and also by including large cell neuroendocrine carcinoma of the lung, which is a really hard to treat pulmonary neoplasm which currently lacks any standardized treatment. So that is really a step forward which we will build on in the future. Dr. Ece Cali: And one thing I would note in this trial, only patients with tumor expressing DLL3 were enrolled. Can you tell us a little bit more about this target, DLL3 in the context of neuroendocrine tumors, and does DLL3 expression predict clinical outcomes after treatment with DLL3 BiTEs, or do we actually need other predictive biomarkers for these novel agents? Dr. Martin Wermke: Yeah, thank you. That's a pretty interesting question. First of all, DLL3 is an atypical notch ligand, which is expressed by the majority of neuroendocrine carcinomas, virtually absent on healthy adult tissues. Therefore, turning it really into a bona fide target for T-cell engaging therapies, pretty low risk for on-target off-tumor side effects. We found that in all the patients we screened, we had an expression rate of about 94% in small cell lung cancer, 80% of large cell neuroendocrine carcinoma of the lung were positive, and also about 80% of the extrapulmonary neuroendocrine carcinoma. So it's really a high prevalence. So the fact that we only included DLL3+ tumors still means we included most of the patients that presented with these diseases. I think at the moment there are no data suggesting a clear-cut association between DLL3 expression levels and outcome on DLL3 CD3 T-cell engagers. There's also not a lot published. If you want to find this out for tarlatamab, you have to look into their patent to really see the data, but it's not clear-cut and I'm sure we need other markers to complement that. And I think what probably plays a major role is intrinsic T-cell fitness. So the question how really diseased your T-cells are, how old you are, because age also correlates with the fitness of the immune system, and other patient characteristics such as tumor burden, we've seen all across the board that the higher the tumor burden, the lower the rate of prolonged response is in such trials. And I also think we need to focus on other components of the tumor microenvironment. So see how high the T-cell infiltration with obrixtamig is and how abundant suppressive elements like regulatory T-cells or myeloid-derived suppressive cells are. That is work which is currently being done. Data are emerging, but I don't think that at the moment we have any clear biomarker helping us to select who should not receive DLL3 T-cell engagers. Dr. Ece Cali: Those are great points and there is a lot we need to learn about how to use these novel agents in the future. I'd like to highlight the results in large cell neuroendocrine carcinoma of the lung. The response rate in this group was remarkably high at 70%. Though we should note the small sample size of only 14 patients in this trial. After first line chemoimmunotherapy, current approved options for this population have very modest clinical activity. Given these trial results, how do you envision the field moving forward for patients with large cell neuroendocrine carcinoma? Dr. Martin Wermke: Yeah, I think LCNEC is really an area which urgently needs further improvement of therapeutic standards. At the moment, as I said, there is no real standard. We are usually extrapolating from results we have in small cell lung cancer or non-small cell lung cancer, but I don't think we have too many prospective trials really informing this. Of course, 14 patients is a small sample size, but I think it's still fair to say that we can claim that DLL3 T-cell engagers are not doing worse in LCNEC than they do in SCLC. And that's why I think we really need to move forward clinical trials that are specifically targeting this population. Although I fear a bit that, given the rareness of this disease and the aggressiveness of its phenotype, that this is probably not the main focus of the pharmaceutical industry. So I think it's up to us academic investigators to really come up with investigator-initiated trials trying to fill the knowledge gaps we have here. Dr. Ece Cali: And one more thing that I want to talk about is the accessibility for these drugs. These novel agents are showing real promise in improving outcomes for patients with high-grade neuroendocrine tumors, an area where progress has been limited until very recently. However, as DLL3 BiTEs become more widely used, issues of logistics and access come into sharper focus. With unique toxicities and the specialized monitoring, their use is restricted to certain centers. Looking ahead, what kinds of strategies could help mitigate some of these adverse events or make these treatments more broadly available? Dr. Martin Wermke: Yeah, I think if you look at countries like the United States where tarlatamab has already been approved, we can see how the management strategies are evolving. I've heard about a colleague equipping their patients with thermometers and a pill of Dexamethasone, alongside with a temperature control protocol and clearly instructing them, "If you measure a temperature above a certain level then start taking the Dexamethasone and come back to our office and we're going to take care of you." I think that's one way to move forward. I think we are lucky in a way that CRS usually manifests within the first 24 hours. This was the same in our study, like in the tarlatamab studies. So we really know when the time of trouble is for our patients. And in this time, I think we need to instruct the patients to stay close to the hospital. I don't think we need to hospitalize all of them, but we probably need them to stay in a nearby hotel to be able to reach the emergency room if needed in a short period of time. And I think we can also learn in this strategy how to manage bispecific antibodies from the experience our colleagues in hematology had because they have been using bispecific T-cell engagers for quite some years right now and they developed strategies and networks that were able to successfully treat these patients also on an outpatient basis. And I think that is clearly an experience we need to follow, acknowledging that we are talking about diseases which are much more frequent than the standard hematology indications. Dr. Ece Cali: Thank you so much, Dr. Wermke, for this informative discussion and for sharing your perspective on this evolving field. Dr. Martin Wermke: Yeah, thank you for providing me with the opportunity to talk about data. It was really great being able to share that, and I really think that we are just at the beginning of a new exciting area for the treatment of neuroendocrine carcinomas, and I think much improvement is yet to come for our patients. Dr. Ece Cali: Yes, that's really exciting. And thank you everyone for listening to JCO Article Insights. Please come back for more interviews and article summaries and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit . The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on this podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Dr. Martin Wermke's Disclosures Honoraria: Lilly, Boehringer Ingelheim, SYNLAB, Janssen, Merck Serono, GWT, Amgen, Novartis, Pfizer, BMS GmbH & Co. KG, Regeneron, MJH/PER, Takeda Consulting or Advisory Role: Bristol-Myers Squib, Novartis, Lilly, Boehringer Ingelheim, ISA Pharmaceuticals, Amgen, immatics, Bayer, ImCheck therapeutics, AstraZeneca, Tacalyx, Regeneron, Daiichi Sankyo Europe GmbH, Zymeworks, PharmaMar, Iovance Biotherapeutics, T-Knife, Genentech Research Funding: Roche Patents, Royalties, Other Intellectual Property Travel, Accommodations, Expenses: Pfizer, Bristol-Myers Squibb, AstraZeneca, Amgen, GEMoaB, Sanofi/Aventis, immatics, Merck Serono, Janssen Oncology, Iovance Biotherapeutics, Daiichi Sankyo Europe GmbH" /episode/index/show/jcopodcast/id/38353490

TTFields in Locally Advanced Pancreatic Adenocarcinoma 09/11/2025

TTFields in Locally Advanced Pancreatic Adenocarcinoma Host Dr. Shannon Westin and guest Dr. Hani Babiker discuss the JCO article "" TRANSCRIPT TTFields in Locally Advanced Pancreatic Adenocarcinoma Dr. Shannon Westin: Hello everyone, and welcome to another episode of , the podcast where we get in depth with manuscripts that have been published in the . I am your host, gynecologic oncologist , social media editor at the JCO, and just excited to be here to learn today about pancreatic cancer. None of our participants have conflicts of interest related to this podcast, and it is my honor to introduce . He is an associate professor of medicine, consultant in oncology at the Mayo Clinic in Jacksonville, Florida. Welcome, Dr. Babiker. Dr. Hani Babiker: Hi, Dr. Westin. Thank you for the great opportunity to discuss our trial, and thank you for having me here. I really appreciate it, and I am excited. Dr. Shannon Westin: All right, so are we. So we are going to be talking about “” This was simultaneously published and presented in the JCO and at the annual meeting of ASCO on 5/31/2025. So, let's level set. Can you speak to us just a little bit about pancreatic cancer? What is the survival, and what is the typical treatment for locally advanced disease? This gynecologic oncologist has not kept up in this field. Dr. Hani Babiker: Absolutely, Dr. Westin, and thank you for that question. Pancreatic adenocarcinoma is a lethal cancer. When I first started my career, the 5-year survival, per the Surveillance, Epidemiology, and End Results, was at 4.5%. I always, whenever I was giving talks, say that I really hope that I will see it in the double digit. Now, the 5-year survival for all pancreatic adenocarcinoma is 13.3%. And the 5-year survival, and although it is a double digit, I still hope that I will see it in a higher double digit in the future. It is even worse in patients with metastatic cancer, about 3% 5-year survival for metastatic pancreatic cancer. It is a dismal diagnosis. I really hope in the future we will find a better therapeutic approach to this lethal cancer. Dr. Shannon Westin: Yes, I just lost a very dear friend and colleague to this disease, so I completely agree with you. Well, now that we are settled kind of with the basics here, I would love to talk a little bit about kind of the primary piece of this intervention, the Tumor Treating Fields. So, how does this work? And what diseases has it gotten indications in as yet? Dr. Hani Babiker: Absolutely. So, Tumor Treating Fields is alternating frequency electrical fields that have been studied preclinically and shown that it abrogates cancer cell proliferation. Earlier on, we knew that it inhibits polymerization of tubulin, and hence, it affects cancer cells from proliferating. Later, we are learning that there are multiple mechanisms of action. It affects permeability, allowing for better drug delivery. It also inhibits cancer cell proliferation through affecting autophagy mechanisms that pancreatic cancer cells will use for proliferating and becoming more aggressive. There is also some early data preclinically in colorectal cancer cell lines and lung cancer cell lines and in vivo models showing that it potentially could activate the microenvironment to make it more pro-immunogenic. We recently published papers showing that it could also affect the nanomechanical properties of the tumor microenvironment within pancreatic cancer, hinting towards affecting, potentially, the stroma. So, there are multiple mechanisms to Tumor Treating Electric Fields. It is a new, novel therapeutic approach. Sometimes when I speak with my trainees, I say, "Well, we have surgery, we have radiation and chemotherapy, and this is something new." Tumor Treating Fields initially was studied in refractory GBM and got an indication there. Subsequently, frontline treatment of GBM in a randomized clinical trial, and then malignant pleural mesothelioma and non-small cell lung cancer. We have studied it in pancreatic cancer. Dr. Shannon Westin: I don't think I have ever heard it described so perfectly. That was brilliant. So thank you, and I hope everyone listening knows that you just got a masterclass on this mechanism. You know, they dabbled in it a little bit in ovarian cancer and it didn't quite make the grade, so I was a little definitely disappointed. But very excited about the data we're going to talk about today. So let's get into the PANOVA-3 study. Can you highlight the overall design and also the key eligibility criteria that would be helpful for our listeners? Dr. Hani Babiker: Absolutely. So, it started off with preclinical work in pancreatic cancer showing Tumor Treating Fields with chemo abrogate cancer cell perforation. It led to a trial, the PANOVA-2 trial, that was run in Europe that showed efficacy for OS and PFS in patients with locally advanced pancreatic cancer, which included metastatic and locally advanced pancreatic cancer, more so in locally advanced that led to the PANOVA-3 trial, which was an international, global study. This was in more than 190 centers, 20 countries in Latin America, North America, Europe, and Asia. It was a randomized trial. Patients were randomized 1 to 1 to either chemotherapy with gemcitabine plus nab-paclitaxel per drug label. The other arm was with Tumor Treating Fields at 150 kHz for a recommendation for patients to wear it 18 hours per day. The primary end point of the trial was OS, overall survival. The secondary end point included other efficacy landmarks such as local PFS, pain control, quality of life, and safety. And there was a post hoc that looked at distant PFS. Dr. Shannon Westin: That's a pretty common secondary end point in pancreatic studies of looking at the pain-free interval. I thought that was really brilliant because, you know, I think in gyn cancers, we see resolution of symptoms as being a really big deal, but it's not necessarily something that we always look at. So I thought that was really nice that you included that. Okay, talk to us a little bit about the population. So, the population that actually got treated in PANOVA-3 is pretty generalizable to what people are treating in the clinic. Dr. Hani Babiker: So, in pancreatic cancer, unfortunately, most of our patients present, approximately 80%, with metastatic disease. Local is divided to resectable, borderline, and locally advanced. We studied this trial, a randomized trial, in locally advanced and unresectable, which is really an unmet need. Most of our patients with locally advanced and unresectable are grouped up with other trials in the metastatic setting without a focus on locally advanced and unresectable, save for a few trials. This year, a trial that we were looking for for a long time, the LAPLACE trial, unfortunately, that we were very excited about, this is a molecule that targeted connective tissue growth factor, that showed earlier efficacy in a randomized trial, did not meet up the median OS end point. And hence, PANOVA-3 is the first trial in locally advanced and unresectable that did meet its primary end point. So, it's a very unmet need in locally advanced and unresectable. A lot of the times, our patients in clinic are treated with frontline chemotherapy that was studied in metastatic disease and locally advanced and unresectable, which include either FOLFIRINOX, NALIRIFOX, or gemcitabine/abraxane. I do have in my clinic multiple patients that would stay on the regimen for such a long time, and then we would have to devise a mechanism of maintenance, although this is not studied really in details, either with capecitabine or dropping the oxaliplatin to continue FOLFIRI. And then we also approach chemoradiotherapy. So the trial was in a disease in pancreatic cancer that really is an unmet need. So the inclusion criteria included a patient with locally advanced and unresectable. These were done at multiple centers. Most of them academic centers were discussed at the tumor board, and if it's unresectable, they will be meeting specific metrics of appropriate liver function tests, kidney function tests, and blood counts. We excluded patients that obviously had, given that these are electric fields, patients that have, for example, stimulators or pacemakers, knowing that this could potentially affect some of these devices. But for the most part, it was locally advanced and unresectable patients with a very good performance status and good counts. Dr. Shannon Westin: That's great. I think everyone's excited to hear about the primary outcome of overall survival. What did you find, and how does it compare to some of the recent trials? Dr. Hani Babiker: We're very excited that it did meet its primary end point of median overall survival. It was very exciting knowing that a lot of us were disappointed a little bit of some of the trials that were presented at ASCO GI, such as the LAPLACE trial that I alluded to. Just before the presentation, the PRODIGE 29 trial that is in locally advanced and unresectable that randomized patients with locally advanced disease to either FOLFIRINOX or single-agent gemcitabine, allowing for a crossover, although it did meet its primary end point of PFS, there was no overall survival benefit. So that kind of got us a little bit disappointed, but having the PANOVA-3 trial being positive in median OS got us all excited. In addition, the 12-year overall survival rate was increased in both the intention-to-treat and modified intention-to-treat. The modified intention-to-treat were patients that have had at least one cycle of therapy with TTFields daily and/or one cycle with chemotherapy, which was gemcitabine plus nab-paclitaxel. There was a trend to improvement in PFS and local PFS, although that did not have statistical significance, but the 12-year PFS rate in both the intention-to-treat and modified intention-to-treat was significant. For me, as one of the investigators, that told me that there might be a specific biomarker that would tell me that patients could respond greater than others, more exceptional than others, given that 12-month PFS rate was improved. On a post hoc analysis, the distant PFS was improved with the intervention of Tumor Treating Fields with gemcitabine plus nab-paclitaxel. In addition, there was an improvement in global health status and quality of life in addition to pain-free survival, which is a strong hurdle in our patients with pancreatic adenocarcinoma that most present with significant abdominal pain. Dr. Shannon Westin: One of the other questions that I think has come up is around central review. So did you all use central review in this study? Dr. Hani Babiker: Most of the centers were academic centers. These were discussed in tumor boards, which included radiation oncologists and surgeons. I wanted to point out that it's very important to note that the primary end point was overall survival. So the primary end point was not PFS. Hence, the central review would help us, for example, with elaborating and making sure patients were actually locally advanced disease, but in a setting where the primary end point is overall survival, that was the key point of the clinical trial. This trial was discussed at academic centers, and all included tumor boards to decide if patients were locally advanced or not. In the trial, there was a good proportion of patients, or percentage, that had a CA 19-9 more than 1000. That could indicate that potentially there are a fraction of patients that actually had metastatic disease, micrometastatic disease. So that could hint towards why the median OS was slightly lower then in both arms when compared to, for example, the trial that was presented at ASCO GI, the LAPLACE trial. However, having said that, we were very excited about the trial. It was the first positive trial in locally advanced and unresectable to meet median OS survival. Dr. Shannon Westin: It's so awesome. So congratulations. Okay, so let's talk a little bit about your very detailed secondary end points because you had a lot of really prudent choices there. So anything that was interesting or informative in those end points? Dr. Hani Babiker: One major hurdle back we have for most of our patients with pancreatic adenocarcinoma, like I mentioned earlier, is pain. We try to approach it, obviously, with narcotics. If it doesn't work, we try to do celiac axis block interventionally, and that sometimes is successful and sometimes is not. So actually, to see the pain-free survival end point to be met was very exciting for us. And as for me, as a scientist that studies TTFields in clinic and lab as also to develop a mechanism and understanding really how that works. That was very important for us that in addition to chemotherapy, it improved pain-free survival or deterioration of pain. And most importantly, our patients with pancreatic cancer, this disease is very aggressive. It affects quality of life of patients. Patients feel fatigued, tired. It's a procoagulant tumor that causes clots and strokes, etcetera, marantic endocarditis. And one big problem we deal with when we're seeing patients in clinic is obviously that quality of life. Although data have shown with treatment, with frontline regimens, that quality of life improves with treatment and chemotherapy, it's actually great to see that that improvement happens early in addition to Tumor Treating Fields. The other interesting point was that it was not only pain and quality of life, but also digestive symptoms that are improved with this intervention, knowing that a lot of our patients do have pancreatic cancer, pancreatic exocrine insufficiency that affect also with digestion, and a lot of our patients have abdominal pain after eating and diarrhea. So it was interesting to see that also improved with the intervention. Dr. Shannon Westin: You have touched a little bit on some of the adverse events, kind of with the TT mechanisms, but I'd love to hear a little bit more detail around adverse events in general in this study, as well as specific AEs related to the Tumor Treating Fields. Dr. Hani Babiker: Absolutely. So when we compared both arms, there was a similar toxicity related to the regimen, mostly with chemotherapy, but in specifically to Tumor Treating Fields, there was a rash, and that included dermatitis and rash. Most of the side effects were grade 1 and grade 2. Grade 3 toxicities related to skin was less than 10%, approximately 7% to 8%, and hence did not affect many patients. But it was something to note, and it's something that in the future, when we develop a mechanism of treating patients to note early. We in our clinic have learned to treat patients in the clinical trial early with topical steroids to each patient, of shifting the arrays to mitigate some toxicity and rash. We do advise our patients in hot areas, we keep them aware that sweating, for example, can lead to higher conductivity of electrical fields with a predisposition for rash. So if there's an opportunity to stay in a little bit of a cold area, make sure that the arrays are shifted, use topical steroids early. If it's a significant rash, to hold treatment for at least 48 hours and speak to the investigators. And through these mechanisms, we have learned that we were able to mitigate the rash quite a bit. Dr. Shannon Westin: That's awesome. Thank you so much. Yeah, I'm, it's summer right now, and I think- I'm in Texas, you're in Florida, like we know. Okay, so I guess, again, you have been kind of touching on this, but I would love to know, like if in the quality-of-life assessments or if just in your discussions with patients, like how easy is this to use? How easy is the Tumor Treating Fields device to use, and what do patients really think? Dr. Hani Babiker: Absolutely. We have learned that whenever we speak with patients, it's always good to discuss with them briefly the science of it. A lot of patients would want to know if it's interventional, is that something that goes, is delivered percutaneously or not, and we explain that these are delivered through arrays that are through the skin. We always touch base with them about a lot of question I get about mechanism of action and then about compliance. So I think one important thing to note is that compliance with the use of the device is a lot of the question we'll get quite a bit. Patients know there's going to take an effort from them, and some of my patients enjoyed it because they felt like they also are fighting the disease by wearing the device. I have learned very quickly that having a team, surrounded by a team that knew how to mitigate some of the side effects and knew how to explain how to use the device helped quite a bit. And this included some of our nurses and our nurse practitioners and our clinical research coordinators who've done a wonderful job of showing these arrays actually to patients before they start on the trial, look at it, know how it works. The other point to know is that the sponsor provided Device Support Specialist, we call them DSS, they have been instrumental in helping us, helping the patients know how to use the device, how to use the generator, how to change the batteries, and that helped us conduct the trials and enroll very well. I would envision in the future with education and relying on the Device Support Specialist and having a team that knows how to use the device and mitigate some of the side effects will go a long way for patients to learn about this treatment. Many of the times our patients said while they are on the clinical trial felt like they are also being part of this team in applying the device and fighting the cancer. Dr. Shannon Westin: That's awesome. Well, I guess the bottom line. Is it ready for prime time? Is this something you are going to use for your patients in the clinic? Dr. Hani Babiker: Absolutely. In a disease that has poor prognosis, and we are trying our best to find new treatments to fight this cancer and treatment modalities, presenting patients with all the treatment options that are out there would be recommended. It's what I would do it for in my clinic. And you know, it's funny that I am mentioning that right now. I had a patient who was seen internationally asking about the trial and the device and had locally advanced and unresectable before they start frontline treatment. I do think that there is going to be an educational piece. Obviously, this is not a pill, it's not an intravenous chemotherapy that we're very well and accustomed to. And some of us in academic centers know it very well. I usually joke that whenever I am talking about it in pancreatic cancer, if there is a radiation oncologist in the room, they will be like, "Yeah, we know all about it. We have been treating patients with GBM over there." So a lot of the times, when we first went to trial, if I had any questions, I would call them and ask them. So from their perspective, they, because they use it as a standard of care in treatment of GBM, they develop significant expertise in it. I think in the GI world, specifically and with oncologists that treat pancreatic cancer and specifically oncologists in the community, learning about the device and how to use it, how to recommend it, how to mitigate side effects, will be hopefully for prime time in the future. Dr. Shannon Westin: That's great. Sounds like some real educational opportunities there. Well, this has been awesome. Thank you so much, Dr. Babiker. I mean, I learned a ton, and I wish that we could find a way to use this in gynecologic cancers, but really, really just want to commend you on the design of the trial and the success in this really devastating disease. So again, this was "." And as always, I am your host, Shannon Westin. Please go wherever you get your podcasts and have an awesome day. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended... /episode/index/show/jcopodcast/id/38147775

JCO at WCLC: Multinational Pivotal Study of Sunvozertinib in Exon20ins NSCLC 09/09/2025

JCO at WCLC: Multinational Pivotal Study of Sunvozertinib in Exon20ins NSCLC JCO fellow Dr. Ece Cali speaks with JCO Associate Editor Dr. Thomas E. Stinchcombe to discuss the JCO article , that was simultaneously released at the IASLC 2025 World Conference on Lung Cancer. TRANSCRIPT Dr. Ece Cali: Hello, and welcome to our series where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year’s most important oncology meetings. I am your host, Dr. Ece Cali, JCO editorial fellow, and I am joined by Dr. Tom Stinchcombe, JCO associate editor, to discuss the Journal of Clinical Oncology article and 2025 World Conference on Lung Cancer abstract presentation, “.” The WU-KONG1B trial is a multinational, phase II study that investigated the efficacy and safety of different doses of sunvozertinib in patients with metastatic non-small cell lung cancer and EGFR exon 20 insertion mutations after progression on platinum based chemotherapy. Tom, before we dive into the results, could you walk us through the rationale for this study, and how does it fit into the current treatment options for patients with EGFR exon 20 insertion? Dr. Tom Stinchcombe: Thank you, Dr. Cali. I think the clinical context is always important. We have known that EGFR exon 20 insertions exist and that they are resistant to our currently available EGFR tyrosine kinase inhibitors, and I think there have been attempts in the past to develop a tyrosine kinase inhibitor, but there is a very narrow therapeutic window between the dose you need to inhibit the EGFR mutation in the cancer and the EGFR receptor on normal tissues, most notably the mucosa, the gut, and the skin. And so, our previous attempts have failed largely because the dose required was not tolerable for patients and they could not really stay on the drug for a long time or they were not very active. And so, I think there was a real desire to develop an EGFR tyrosine kinase inhibitor, and then, historically, the standard had been a platinum based doublet as the standard of care. And more recently, platinum based doublet with amivantamab has proven to be superior to platinum based chemotherapy alone. I think the context is also important that amivantamab is not necessarily available in all the countries, and so, there are patients who do not have access to amivantamab. Going to the rationale, I think that this drug had shown preliminary promise of having activity but without that being encumbered by those EGFR wild type toxicities, and, therefore, it was really explored in this larger study. Dr. Ece Cali: And what are some key findings from this trial? Dr. Tom Stinchcombe: So, I think that we should look at the study design. It is a little quirky, for lack of a better term, in that there is a randomization to 200 versus 300 mg, and then, there was a nonrandomized cohort of 300 mg. So, when you look at the study, if you are a purist, you will just look at the randomized patients. If you are sort of an aggregator, you look at all patients. So, it shows reporting on three cohorts, but I think the key findings are that the 200 mg and the 300 mg treatments had similar toxicities in terms of response rate, duration of response, and progression free survival. And as you know going through the review, there was a lot of queries from the reviewers as to which would be the preferred dose, and to me, I think this really illustrates a dose finding component to a trial design because there is a lot of debate about what the minimal effective dose is or the optimal dose. And in this case, having the two dose cohorts did provide us some valuable efficacy and toxicity information. And then, when I look at the study, I want to make sure it reflects my patient population, and about a quarter of patients had brain metastases, and about 15% had previous amivantamab, and about 5% to 10% had another EGFR tyrosine kinase inhibitor. Dr. Ece Cali: And what is the objective response rate and the duration of response? These are pretty good numbers for this patient population. Dr. Tom Stinchcombe: In the 200 mg cohort, it was about 46%. The duration of response was around 11 months, and the PFS was around 8 months. The 300 mg cohort was 46%, duration of response 9.8, and the median PFS is 6.9 months, and I think that this is greater activity than we have seen with our previous attempts at EGFR tyrosine kinase inhibitors. Dr. Ece Cali: And based on these data, FDA granted accelerated approval for sunvozertinib very recently at 200 mg once daily dosing in this setting. So, that is a major step forward for our patients. Dr. Stinchcombe, how does this impact your clinical practice, and what side effects should oncologists be watching for if they prescribe this medication? Dr. Tom Stinchcombe: So, I think it was very interesting that they chose the 200 mg dose, which I think was more tolerable, and when we kind of look at this, there still was a rate of diarrhea, all grade, rash, paronychia, which are the EGFR related toxicities. There can be some decreased appetite, stomatitis, and then, it can lead to some lab abnormalities, like increased CPK and creatinine that physicians have to be aware of. You know, how it will affect my practice is that all these patients had received a platinum based chemotherapy as the first line therapy. I think that this would become my preferred second line therapy for patients outside the context of a trial because of the activity and the tolerability. Dr. Ece Cali: And lastly, several other tyrosine kinase inhibitors are being evaluated for EGFR exon 20 insertion, including in the frontline setting. So, what are some of the outstanding questions in this space, and what data should our listeners keep an eye on moving forward? Dr. Tom Stinchcombe: I think you are right that now, there is going to be another EGFR tyrosine kinase that may become available in the next year, and there is another drug, furmonertinib, that is being investigated. I think, for the clinical question, is, well, can we move these into the first line setting? And actually, the development path has two ways of doing this. There is EGFR tyrosine kinase compared to platinum based chemotherapy, and then, platinum based chemotherapy with an EGFR tyrosine kinase versus platinum based chemotherapy, and both have their merits and strengths. And so, I think it is going to be very interesting as we see if those first line trials, one, can they be demonstrated to be superior to platinum based chemotherapy, and then by what magnitude and what the side effects are. But I think we are hoping that in the next couple of years, we will have an additional first line option for our patients. Dr. Ece Cali: Yeah, it is always great to have more options for our patients. Thank you, Dr. Stinchcombe, for speaking about the JCO article, “Phase II Dose-Randomized Study of Sunvozertinib in Platinum-Pretreated Non-Small Cell Lung Cancer With EGFR Exon 20 Insertion Mutations.” Join us again for the latest JCO simultaneous publications. Please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of World Lung Conference. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. /episode/index/show/jcopodcast/id/38063520

Racial and Ethnic Disparities Among Medicare Beneficiaries 08/28/2025

Racial and Ethnic Disparities Among Medicare Beneficiaries Host Davide Soldato and guest Dr. John K. Lin discuss the JCO article "." TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Davide Soldato: Hello, and welcome to , the podcast where we sit down with authors of the latest articles published in the . I'm your host, Dr. Davide Soldato, a medical oncologist at Ospedale San Martino in Genoa, Italy. Today, we are joined by Dr. Lin, assistant professor in the Department of Health Services Research at the University of Texas MD Anderson Cancer Center. Dr. Lin and I will be discussing the article titled, "." Thank you for speaking with us, Dr. Lin. Dr. Lin: Thank you so much for having me. I appreciate it. Dr. Davide Soldato: So, just to start, to frame a little bit the study, I just wanted to ask you what prompted you and your team to look specifically at this question - so, racial and ethnic disparities within this specific population? And related to this question, I just wanted to ask how this work is different or builds on previous work that has been done on this research topic. Dr. Lin: Yeah, absolutely. Part of the impetus for this study was the observation that despite people who are black or Hispanic having equivalent health insurance status - they all have Medicare Fee-for-Service - we've known that treatment and survival differences and disparities have persisted over time for patients with metastatic breast, colorectal, lung, and prostate cancer. And so, the question that we had was, "Why is this happening, and what can we do about it?" One of the reasons why eliminating racial and ethnic disparities in survival among Medicare beneficiaries with metastatic cancer has been elusive is because these disparities are occurring along a lot of dimensions. Whether or not it's because the patient presented late and has very extensive metastatic cancer; whether or not the patient has had a difficult time even seeing an oncologist; whether or not the patient has had a difficult time starting on any systemic therapy; or maybe it's because the patient has had a difficult time getting guideline-concordant systemic therapy because, more recently, these treatments have become so expensive. Disparities, we know, are occurring along all of these different facets and areas of the treatment cascade. Understanding which one of these is the most important is the key to helping us alleviate these disparities. And so, one of our goals was to evaluate disparities along the entire treatment cascade to try to identify which disparities are most important. Dr. Davide Soldato: Thank you very much. That was very clear. So, basically, one of the most important parts of the research that you have performed is really focusing on the entire treatment cascade. So, basically, starting from the moment of diagnosis up to the moment where there was the first line of treatment, if this line of treatment was given to the patient. So, I was wondering a little bit, because for this type of analysis, you used the SEER-Medicare linked database. So, can you tell us a little bit which was the period of time that you selected for the analysis? Why do you think that that was the most appropriate time to look at this specific question? And whether you feel like there is any potential limitation in using this type of database and how you handled this type of limitations? Dr. Lin: Yeah, absolutely. It's a great question. And I want to back up a little bit because I want to talk about the entire treatment cascade because I think that this is really important for our research and for future research. We weren't the first people to look at along the treatment cascade for a disease. Actually, this idea of looking along the treatment cascade was pioneered by HIV researchers and has been used for over a decade by people who study HIV. And there are a lot of parallels between HIV and cancer. One of them is that with HIV, there are so many areas along that entire treatment cascade that have to go right for somebody's treatment to go well. Patients have to be diagnosed early, they have to be given the right type of antiretrovirals, they have to be adherent to those antiretrovirals. And if you have a breakdown in any one of those areas, you're going to have disparities in care for these HIV patients. And so, HIV researchers have known this for a long time, and this has been a big cornerstone in the success of getting people with HIV the treatment that they need. And I think that this has a lot of parallels with cancer as well. And so, I am hoping that this study can serve as a model for future research to look along the entire treatment cascade for cancer because cancer is, similarly, one of these areas that requires multidisciplinary, complex medical care. And understanding where it is breaking down, I think, is crucial to us figuring out how we can reduce disparities. But for your question about the SEER-Medicare linked database, so we looked between 2016 and 2019. That was the most recent data that was available to us. And one of the reasons why we were excited to look at this is because there were some new treatments that were just released and FDA-approved around 2018, which we were able to study. And this included immunotherapy for non–small cell lung cancer, and then it also included androgen receptor pathway inhibitors, the second-generation ones, for prostate cancer. And the reason why this is important is because for some time, as we have developed these new therapies, there's been a lot of concern that there have been disparities in access to these novel therapies because of how expensive they are, particularly for the Medicare population. And so one of the reasons why we looked specifically at this time period was to understand whether or not, in more recent years, these novel therapies, people are having increasing disparities in them and whether or not increasing disparities in these more expensive, newer therapies is contributing to disparities in mortality. That being said, obviously, we're in 2025 and these data are by now six years old, and so there are additional therapies that are now available that weren't available in the past. But I think that, that being said, at least it's sort of a starting point for some of the more important therapies that have been introduced, at least for non–small cell lung cancer and prostate cancer. And the database, SEER-Medicare, is helpful because it uses the population cancer registry, which is the SEER registry cancer registry, linked to Medicare claims. So, any type of medical care that's billed through Medicare, which is going to basically be all of the medical care that these patients receive, for the most part, we're going to be able to see it. And so, I think that this is a really powerful database which has been used in a lot of research to understand what kind of care is being received that has been billed through Medicare. So, one of the limitations with this database is if there is care that's received that was not billed through Medicare, we're not going to be able to see that. And this does not happen probably that frequently, particularly because most patients who have insurance are going to be receiving care through insurance. However, we may see it for some of the oral Part D drugs. Some of those drugs are so expensive that patients cannot pay for the coinsurance during that time. And it's possible that some of those drugs patients were getting for free through the manufacturer. We potentially missed some of that. Dr. Davide Soldato: So, going a little bit into the results, I think that these are very, very interesting. And probably the most striking one is that when we look at the receipt of any type of treatment for metastatic breast, colorectal, prostate, and lung cancer - and specifically when we look at guideline-directed first-line treatments - you observed striking differences. So, I just wanted you to guide us a little bit through the results and tell us a little bit which of the numbers surprised you the most. Dr. Lin: So, what we were expecting is to see large disparities in receiving what we called guideline-directed systemic therapy. And guideline-directed systemic therapy during this time kind of depended on the cancer. So, we thought that we were going to see large disparities in guideline-directed therapy because these were the more novel therapies that were approved, and thus they were going to be the more expensive therapies. And so, what this meant was for colorectal cancer, this was going to be any 5-FU–based therapy. For lung cancer, this was going to be any checkpoint inhibitor–based therapy. For prostate cancer, this was going to be any ARPI, so this was going to be things like abiraterone or enzalutamide. And for breast cancer, this was going to be CDK4 and 6 TKIs plus any aromatase inhibitor. And so, for instance, for breast, prostate, and lung cancer, these were going to be including more expensive therapies. And so, what we expected to see was large disparities in receiving some of these more expensive, novel therapies. And we thought we were going to see fewer disparities in receiving some of the cheaper therapies, such as aromatase inhibitors, 5-FU, older platinum chemotherapies for lung cancer, and ADT for prostate cancer. We were shocked to find that we saw large racial and ethnic disparities in seeing some of the older, cheaper chemotherapies and hormonal therapies. So for instance, for breast cancer, 59% of black patients received systemic therapy, whereas 68% of white patients received systemic therapy. For colorectal, only 23% of black patients received any systemic therapy versus 34% of white patients. For lung, only 26% of black patients received any therapy, whereas 39% of white patients did. And for prostate, only 56% of black patients received any systemic therapy versus 77% of white patients. And so, we were pretty shocked by how large the disparities were in receiving these cheap, easy-to-access systemic therapies. Dr. Davide Soldato: Thank you very much. So, I just wanted to go a little bit deeper in the results because, as you said, there were striking differences even when we looked at very old and also cheap treatments that, for the majority of the patients that were included inside of your study, were actually basically available for a very small price to these patients who had the eligibility for Medicare or Medicaid. And I think that one of the very interesting parts of the research was actually the attention that you had at looking how much of these disparities could be explained by several factors. And actually, one of the most interesting results is that you observed that low-income subsidy status was actually a big determinant of these disparities in terms of treatment. So, I just wanted to guide us a little bit through these results and then just your opinion about how these results should be interpreted by policymakers. Dr. Lin: Yeah, absolutely. I'm going to explain a little bit about what low-income subsidy status is and dual-eligibility status. Some of the listeners may not know what low-income subsidy status or dual-eligibility status is. Low-income subsidy status is part of Medicare Part D. Medicare Part D is an insurance benefit that allows patients to receive oral drugs. So these are drugs that are dispensed through the pharmacy, such as the CDK4/6 inhibitors, as well as second-generation ARPIs in our study. For patients who have Medicare Part D and whose income is low enough - falls below a certain federal poverty level threshold - those patients will receive their oral drugs for much cheaper. And this is really important for some of these more novel therapies because for some of these more novel therapies, if you don't have low-income subsidy status, you may be paying thousands of dollars for a single prescription of those drugs. Whereas if you have low-income subsidy status, you may be paying less than $10. And so that difference, greater than $1,000 or $2,000 versus less than $10, one would think that the patient who's paying less than $10 would be much more likely to receive those therapies. So that's low-income subsidy status. Low-income subsidy status, importantly, doesn't apply for infused medications like immunotherapy. But it's important to know that most people with low-income subsidy status - about 88% - are also dual-eligible. What dual-eligible means is that they have both Medicare and Medicaid. Medicare being the insurance that everybody has in our study who's greater than 65. And Medicaid is the state-run but federally subsidized insurance that patients with low incomes have. And so patients who are dual-eligible - and about 87% of those with low-income subsidy status are dual-eligible - those patients have both Medicaid and Medicare, and they basically pay next to nothing for any of their medical care. And that's because Medicare will reimburse most of the medical care and the copays or coinsurance are going to be covered by Medicaid. So Medicaid is going to pick up the rest of the bill. So, most of the patients who have low-income subsidy status who are dual-eligible, these patients pay almost nothing for their medical care - Part B or Part D, any of their drugs. And so, one would expect that if cost were the main determinant of disparities in cancer care, then one would expect that dual-eligibles, most of them would be receiving treatment because they're facing minimal to no costs. What we found is that when we broke down the racial and ethnic disparity by a number of factors - including LIS status/dual eligibility, age, the number of comorbidities, etcetera - what we found was that the LIS or dual-eligibility status explained about 20% to 45% of the disparities that we saw in receiving treatment. And what that means is despite these patients paying next to nothing for their drugs, these are the most likely patients to not be treated for their cancer at all. So they're most likely to basically be diagnosed, survive for two months, see an oncologist, and then never receive any systemic therapy for their cancer. And this is not just chemotherapies for colorectal or lung cancer. This includes cheaper, easier-to-tolerate hormonal therapies that you can just take at home for breast cancer, or you can get every six months for prostate cancer, that people who even have poorer functional status are able to take. However, for whatever reason, these dual-eligible or LIS patients are very unlikely to receive treatment compared to any other patient. The low likelihood of treating this group of patients, that explains a large portion of the racial and ethnic disparities that we see. Dr. Davide Soldato: And one thing that I think is very interesting and might be of potential interest to our listeners is, did you compare survival outcomes in these different settings? And did you observe any significant differences in terms of racial and ethnic disparities once you saw that there was a significant difference when looking at both receipt of any type of treatment and also guideline-directed treatments? Dr. Lin: We saw that there were large disparities in survival by race and ethnicity when you look overall. However, when you just account for the patients who received any systemic therapy at all - not just guideline-directed systemic therapy - those differences in survival essentially disappeared. And so, what that suggests is that if black patients were just as likely to receive any systemic therapy at all as white patients, we would expect that the survival differences that we were seeing would disappear. And this is not even just looking at guideline-directed systemic therapy. This was looking just at systemic therapy alone. And so, while guideline-directed systemic therapy should be a goal, our research suggests that if we are to close the gap in disparities in overall survival among black and white patients, we must first focus on patients just receiving any type of treatment at all. And that should be the very first focus that policymakers, that leaders in ASCO, that health system leaders, that physicians, that we should focus on: just trying to get any type of treatment to our patients who are poorer or black. Dr. Davide Soldato: Thank you very much. And this was not directly related to the research that you performed, but going back to this very point - so, increasing the number of patients that receive any kind of systemic treatment before looking at guideline-directed treatments - what would you feel would be the best way to approach this in order to decrease the disparities? Would you look at interventions such as financial navigation or maybe improving referral pathways or providing maybe more culturally adapted information to the patients? Because in the end, what we see is disparities based on racial and ethnicity. We see that we can reduce these disparities if we get these patients to the treatment. But in the end, what would you feel is the best way to bring patients to these types of treatments? Dr. Lin: I think the most important thing is to understand that these disparities are not primarily happening because of the high cost of cancer treatment. These disparities are happening because of other social vulnerabilities that these patients are facing. And so these vulnerabilities could be a lot of things. It could be mistrust of the medical system. It could be fear of chemotherapy or other treatments. It could be difficulty taking time off of work. It could be any number of things. What we do know is when we've looked at the types of interventions that can help patients receive treatment, navigation is probably the most effective one. And the reason why I think that is because when patients don't receive treatment because of social vulnerability, I sort of look at social vulnerability like links in a chain. Any weakest link is going to result in the patient not receiving treatment. This may be because they have a hard time taking time off of work. This may be because they had a hard time getting transportation to their physician. It may be because they had an interaction with a physician, but that interaction was challenging for the patient. Maybe they mistrusted the physician. Maybe they're worried about the medical system. If any of these things goes wrong, the patient is not going to be treated. The patient navigator is the only person who can spot any of those weak links within the chain and address them. And so, I think that the first thing to do is to get patient navigation systems in place for our vulnerable patients throughout the United States. And this is incredibly important because in Medicare, patient navigation is reimbursable. And so this is not something that's ‘pie in the sky’. This is something that's achievable today. The second thing is that it's really important that we see these vulnerabilities happening for patients who are dual-eligible, who have both Medicare and Medicaid. One of the reasons why this is important is because there has been a lot of research outside of what we've done that has shown vulnerabilities for dual-eligible patients who have Medicare for a number of different diseases. And the reason why is because, although patients are supposed to have the benefits of both Medicare and Medicaid, usually these two insurances do not play nicely together. It creates a huge, bureaucratic, complex mess and maze that most of these patients are unable to navigate. And so many of these patients are unable to actually receive the full reimbursement from both Medicare and Medicaid that they should be getting because those two insurers are not communicating well. And so the second thing is that national cancer organizations need to be supporting policies and legislation that is already being discussed in Congress to revamp the dual-eligible system so that it... /episode/index/show/jcopodcast/id/37968315

JCO Article Insights: Lymph Node Dissection for Lung Cancer 08/25/2025

JCO Article Insights: Lymph Node Dissection for Lung Cancer In this JCO Article Insights episode, Dr. Joseph Matthew interviews authors Dr. Yang Zhang and Dr. Haiquan Chen about their recently published JCO article, "" TRANSCRIPT Joseph Mathew: Welcome to the episode for the August issue of the . This is Joseph Mathew, editorial fellow for JCO, and today, it is my pleasure to have with us Dr. Haiquan Chen and Dr. Yang Zhang, authors of the recently published manuscript, "," which we will be discussing today. Dr. Chen is the Director of the Institute of Thoracic Oncology at Fudan University and the Chief of Thoracic Surgery at Fudan University Shanghai Cancer Center, where he is also the Head of Thoracic Oncology MDT and the Director of the Lung Cancer Center. Dr. Chen is a surgeon-scientist and a pioneer in developing individualized surgical strategies for early-stage non-small cell lung cancer. Dr. Zhang is a surgical oncologist and a member of the team which Dr. Chen leads at the Fudan University Shanghai Cancer Center. Welcome Dr. Chen and Dr. Zhang. Thank you very much for accepting our invitation and joining us today as part of this podcast episode. To summarize the salient points, this study presented the interim analysis of a multi-center, open-label, non-inferiority, randomized controlled trial investigating the necessity of systematic mediastinal lymph node dissection at the time of segmentectomy or lobectomy in patients with clinical stage T1N0M0 ground-glass opacity-dominant invasive lung adenocarcinoma, as defined by a consolidation-to-tumor ratio of 0.5 or less on thin-section computed tomography and a maximum tumor diameter of 3 cm or less. Eligible participants with intraoperatively confirmed invasive adenocarcinoma on frozen section analysis were randomized to either the systematic mediastinal lymph node dissection arm or to no mediastinal lymph node dissection. In the latter experimental group, mediastinal lymph nodes comprising the N2 nodal stations were not dissected, and the hilar nodes were variably addressed at the discretion of the operating surgeon. The primary endpoint of the trial was disease-free survival at 3 years. Secondary endpoints included perioperative outcomes, the status of lymph node metastasis in the systemic lymph node dissection arm, and 3-year overall survival. Before the trial reached its accrual target, a pre-planned interim safety analysis set for the time point when enrollment reached 300 patients was performed. It was noted that while none of the patients in either arm had nodal metastasis on postoperative pathological evaluation, lymph node dissection-related intraoperative and postoperative complications were more commonly observed in the systematic lymph node dissection arm, including one life-threatening episode of massive bleeding. Since this met the predefined criteria for trial termination, and in accordance with the principle of non-maleficence, further recruitment was stopped and the trial terminated. Although the 3-year disease-free survival and the overall survival for the enrolled patients were comparable, operative outcomes, including the duration of surgery, blood loss, chest tube duration, length of postoperative stay, and the rate of clinically significant complications, were significantly lower in the experimental arm compared with the systematic lymph node dissection group. The authors concluded that for well-selected patients, mediastinal nodal dissection could be omitted without adversely affecting oncological outcomes, representing a significant shift in current surgical practice, given that guidelines the world over recommend systematic lymph node dissection or sampling for all invasive lung cancers. In summary, this study addressed a clinically relevant question with regard to the extent of nodal dissection, especially in the light of recent evidence recommending less extensive parenchymal dissections for early-stage non-small cell lung cancer, with the findings suggesting that invasive lung adenocarcinoma associated with ground-glass opacities of consolidation-to-tumor ratio up to 0.5 was an excellent predictor of tumor biology, and in clinical T1N0M0 lesions, a reliable predictor of negative mediastinal lymph node involvement. So Dr. Chen and Dr. Zhang, could you tell us some more about what led you to do this research and the challenges which you faced while recruiting patients for this trial? Dr. Yang Zhang: Dr. Mathew, thank you for your summary. The current clinical guidelines recommend systematic lymph node dissection or sampling for every patient with early-stage lung cancer, regardless of their lymph node status. And in our clinical practice, we observe that this procedure causes a lot of surgical complications including chylothorax and recurrent laryngeal nerve injury. Furthermore, dissecting the tumor-draining lymph nodes actually may potentially damage the body's anti-tumor immunity. So, Dr. Chen proposed the concept of selective lymph node dissection, which we aimed to dissect the metastatic lymph nodes, while at the same time we try to preserve as many uninvolved lymph nodes as possible. So previously, we have conducted a series of retrospective studies to identify reliable predictors of nodal negative status in certain mediastinal zones, and we have performed a prospective observational phase 2 clinical trial to validate that the six criteria we proposed are 100% in predicting node-negative status. And this forms the basis for our phase 3 clinical trial. Dr. Haiquan Chen: This trial is only one of the series of trials. The meaning of this trial you already said. And for a long time, from the surgeon's point of view, we considered minimally invasive surgery. It minimizes the size of the incision and minimizes the number of the holes we made. So, the true and the high-impact of minimally invasive, we make a concept of minimal dissection, that means organ-level minimally invasive. So we proposed the concept of minimally invasive 3.0, that means minimal incision, minimal dissection (that means organ-level minimal), and systemic minimally invasive. So at first, we judged from the point of minimally invasive surgery. As long as immunotherapy is widely used in the clinical practice, we know immunotherapy, that means you use drugs to stimulate and activate the lymph node site. If we dissect all the metastatic lymph nodes, cut them out, how can we restimulate that lymph node site? So, from minimally invasive trauma and second, from the functional aspect, to try to save as many uninvolved lymph nodes as possible. Joseph Mathew: Thank you, Dr. Chen. That's a very interesting concept that you alluded to even in the discussion of this paper, as to the potential role of the non-metastatic lymph nodes as immune reservoirs. So, coming back to this paper, were there any challenges which you faced while recruiting patients for this trial? Dr. Haiquan Chen: The criteria is very clear. That means invasive adenocarcinoma, that means most of the centimeter is 3.0 centimeter and also CTR ratio less than 0.5. And we can see that, you know, we did study about that. Even the invasive component of the subsolid nodule, it's bigger than the solid part. That means even the pure GGO, we can find out that there's still some invasive component. From this point of view, pure GGO and subsolid GGO, from this part of invasive carcinoma, that means it's a special clinical subtype that we, from retrospective study and also prospective study, we find out this group of patients, there are no mediastinal lymph node metastasis. So I think it's very important for this kind of group that we can avoid doing the mediastinal lymph node dissection. And we can do organ-level minimally invasive surgery. And also, we try to keep the patient's immune function as normal as possible. Dr. Yang Zhang: Well, Dr. Mathew, we believe that the biggest challenge when we are enrolling these patients is that there needs to be a paradigm shift in the mind because systematic lymph node dissection has long been the standard of care. And some patients may misunderstand. Before the enrollment, we have to give them informed consent, but if the patient hears that they may be enrolled in the no-lymph-node-dissection group, they may feel that they do not receive radical, curative-intent surgery. So we believe, as Dr. Chen has said, after the release of our results, the no-lymph-node dissection may be incorporated in the future guideline for those patients without lymph node involvement, we can just omit the lymph node dissection. Joseph Mathew: The study described two pre-planned interim points during the course of subject enrollment when the data was analyzed. So Dr. Chen and Dr. Zhang, could you please explain a little more about these two interim points of analysis that were planned and the rationale behind it? Dr. Yang Zhang: When conducting this trial, we have two concerns. One is if there is any lymph node metastasis, there may be omission of metastatic lymph nodes not dissected in the no-lymph-node-dissection group. And there is another concern is that if all these lymph nodes are uninvolved, then dissecting these lymph nodes may cause life-threatening complications. So, we set the 150 interim analysis to ensure that there is no lymph node involvement in this group. And the other early termination criteria is set because if there is no lymph node involvement found in both groups, then a severe complication which is life-threatening is unacceptable because it threatens the patient's safety. Joseph Mathew: So, although you did briefly allude to in the paper, what was the basis for selecting DFS as the primary endpoint when the objective of this trial was to assess nodal involvement in this subset of tumors? Dr. Yang Zhang: Well, previously, we have done a series of retrospective studies and one prospective phase 2 trial. And in these studies, we have identified that GGO-dominant lung adenocarcinoma, even if it's invasive, it has no lymph node involvement. So this phase 3 trial was primarily designed to compare the survival outcomes. But as the trial went on, as Dr. Chen has concerns that if the patients have no lymph node metastasis at all, it may be unfair to dissect the lymph nodes for patients enrolled in the systematic lymph node dissection group. So there is one life-threatening complication that happens due to dissecting the lymph nodes and injury to the superior vena cava, which leads to massive bleeding. It is at this point that we decided to terminate this trial for patient safety concerns. Joseph Mathew: Yeah, that's a very fair point. So you made sure that the ethical considerations were kept intact. So another point was, there was a mention in the study of the historical data from your institution suggesting a 3-year disease-free survival of 96.6% for patients with clinical T1N0M0 ground-glass opacity-dominant invasive lung adenocarcinoma. So could you please elaborate on the patterns of recurrence which you noted for this group of patients who had developed a recurrence? Dr. Haiquan Chen: Yeah, I think over 90% 3-year DFS, that's the least. From our retrospective data for this kind of group of patients, their DFS is so good. To the best of my knowledge, almost 100%. So this is very conservative, 94, 90% is very conservative. I think the trial eventually would have been positive. It's a special clinical subtype, even for invasive adenocarcinoma, their prognosis is much better than the other type of invasive adenocarcinoma. Joseph Mathew: So this question may be slightly outside the purview of this study, but in your clinical practice, would you advocate either segmentectomy or lobectomy for all patients meeting the trial criteria, that is, lesions measuring 3 cm or less with a CTR of up to 0.5? Or is there a subgroup of patients you would recommend a wedge dissection for? Dr. Haiquan Chen: I think CTR ratio is one parameter and also the location is another very important parameter. So we put it together to make a decision, the patient should do a lobectomy or segmentectomy. Even for an ongoing trial, for even the patient, invasive adenocarcinoma, we can do in the right location, even wedge, it can achieve enough negative margin in the ongoing trial to verify the comparable result for the patient, we can do the wedge dissection. So not just the CTR ratio, that's not the only parameter to make a decision on what kind of procedure we'll do. Joseph Mathew: Yeah, great point, Dr. Chen. So from my perspective, this study was a well-designed, randomized control trial based on a relevant and clinically valid research question. So what, in your opinion, are the main strong points of this study? Dr. Yang Zhang: We believe that this study represents the first randomized clinical trial published, yet, regarding the topic of selective lymph node dissection. It basically offers the highest level of evidence. We believe our results should be incorporated in the future clinical guideline. Joseph Mathew: Given the increasing incidence of these lesions, I think it was- a randomized control trial in this arena was much awaited. And the other point is that GGO-dominant lung adenocarcinomas, the specific clinical guidelines are not very clear. So I think your study brought out that lymph node dissection for these tumors which satisfy the eligibility criteria could be omitted safely. Important consideration here is that the conclusions of the trial were based on an interim analysis, and this analysis was not planned for an early assessment of the primary endpoint. In other words, the study was not adequately powered to detect a significant difference in DFS at 3 years. So Dr. Chen and Dr. Zhang, what do you perceive are the most important limitations of this study which you feel should be addressed in future research? Dr. Haiquan Chen: So the surgery now is more individualized. I think the surgery from the last two decades, from the maximum tolerable intervention to minimum effective treatment, there's a big shift. So I think that the consensus, we can preserve normal lung parenchyma as much as possible. For the lymph nodes, I think that the big shift, we should shift it to keep as many as uninvolved lymph nodes as possible. So that's very important, not just to reduce the intraoperative trauma, but also to keep the immune environment as normal as possible. Joseph Mathew: Another point was the limited long-term follow-up data to determine the actual impact of omitting lymph node dissection on local-regional disease control. So is any future follow-up planned to assess the long-term survival outcomes for the 302 patients which were enrolled in this trial? Dr. Haiquan Chen: Yeah, I think that's very important for us. This trial we terminated just because if we keep the trial going, it's unfair for the mediastinal lymph node dissection group. We tried to just stop here, and we shifted to the single-arm trial. So, 2 or 3 years, this trial and another trial, they will give our final result to demonstrate more if selective mediastinal lymph nodes have a better result than ever before. And we will support the mediastinal lymph node dissection. That's one way. And the American College just asked me, how can we put this policy into clinical practice in the United States? Because most of the patients they meet have solid tumors. So we have another trial, try to figure out how we can make sure before and intraoperative the lymph node status is negative or positive, and then we can solve that problem and put this policy into clinical practice in the Western society. Joseph Mathew: Great. So that would be something we should all be looking forward to. So, this brings me to the final point of discussion on future research in this field. Dr. Chen, you commented in the paper that future studies should focus on improving the reproducibility of CTR evaluation. What are your thoughts on this subject? Dr. Haiquan Chen: The CTR ratio, the concept from the JCOG 0201, just a concept from that prospective study, the phase 2 study, only subgroup analysis they give the concept of CTR ratio and the diameter. How can we reproduce? In our group and also I believe in Japan and in China, in Korea, and in our daily practice, I think CTR ratio is not a big issue. There are two very important things. One, you make sure the CTR ratio, not in a common CAT scan, but in a high-resolution CAT scan. So the imaging, that's the first thing. And the second, not from the single section and a two or three section, you make sure that your calculation is accurate. That's not just the single section, you make sure that you got the conclusion, the CTR ratio is the same number. We make sure that totally we, from the top to the bottom of the whole lesion, we make sure that the CTR ratio is accurate. Joseph Mathew: Thank you, Dr. Chen. I think that would involve training our radiologists also to be aware of the CTR ratio and how it should be interpreted. So another very interesting concept which you had alluded to in the discussion was the potential role of non-metastatic lymph nodes as immune reservoirs. So how do you think we could preserve these nodes and do you think sentinel node biopsies would play a role in future? Dr. Yang Zhang: Actually, Dr. Chen has also led some basic research on this topic. We are investigating the immunological role of the tumor-draining lymph nodes. And our preliminary results have already shown that the tumor-draining lymph nodes of lung cancer, especially those uninvolved lymph nodes, have a vital role in the anti-tumor immunity and also effective response to the current anti-PD-1 immunotherapy. In the future, we believe that by incorporating our clinical evidence and those findings from our basic research, we will be able to provide very strong rationale to support selective lymph node dissection. Joseph Mathew: So lastly, what are the questions that still remain to be answered and what do you perceive as the next step in this field? Dr. Haiquan Chen: I think for the lung cancer surgery, especially for the cT1N0M0, they are more individualized. We can, based on the patient, the location, the CTR ratio, we can do wedge dissection, or segmentectomy, or lobectomy. For the lymph node dissection, we can do no mediastinal lymph node dissection or selective, only to dissect the positive one, or we have to do the systemic mediastinal lymph node dissection. So we can see there are too many combinations. So in the near future, for the surgery perspective, we have it more individualized. In the future, we just try to make sure we do not cut as many as possible. We just make sure that we can avoid over-diagnosis or overtreatment or over-dissected. I think that in the near future, that goal will come true. Joseph Mathew: That's a great point, Dr. Chen. So that would be something also for the thoracic oncology community to work towards. This wraps up today's episode of . Dr. Chen and Dr. Zhang, thank you very much for taking the time to join us today in what has been a very insightful session. Dr. Haiquan Chen: Thank you. Dr. Yang Zhang: Thanks. Joseph Mathew: To our audience, thank you for listening. Please stay tuned for more interviews and articles, summaries, and be sure to leave us your comments and ratings. For more podcasts and episodes from ASCO, please visit . The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. /episode/index/show/jcopodcast/id/37926345

JCO Article Insights: IMS-IMWG Consensus on High-Risk Multiple Myeloma 07/28/2025

JCO Article Insights: IMS-IMWG Consensus on High-Risk Multiple Myeloma In this JCO Article Insights episode, Michael Hughes summarizes “International Myeloma Society and International Myeloma Working Group Consensus Recommendations on the Definition of High-Risk Multiple Myeloma" by Avet-Loiseau et al. published on June 09, 2025 along with an interview with author Dr Nikhil C. Munshi, MD. TRANSCRIPT Michael Hughes: Welcome to this episode of . This is Michael Hughes, JCO’s editorial fellow. Today I am interviewing Dr. Nikhil Munshi on the “” by Avet-Loiseau et al. At the time of this recording, our guest has disclosures that will be linked in the transcript. While some patients with multiple myeloma live for decades after treatment, others exhibit refractory or rapidly relapsing disease irrespective of treatment administered. We term this “high-risk myeloma.” Multiple risk stratification systems have been created, starting with the Durie-Salmon system in 1975 and evolving with the advent of novel therapeutics and novel treatment approaches. In 2015, the Revised International Staging System (R-ISS) was introduced, which incorporated novel clinical and cytogenetic markers and remained, until recently, a mainstay of risk stratification in newly diagnosed disease. Myeloma as a field has, just in the past few years, though, undergone explosive changes. In particular, we have seen groundbreaking advances not only in treatments - the introduction of anti-CD38 agents and the advent of cellular and bispecific therapies - but also in diagnostic technology and our understanding of the genetic lesions in myeloma. This has led to the proliferation of numerous trials employing different definitions of high-risk myeloma, a burgeoning problem for patients and providers alike, and has prompted attempts to consolidate definitions and terminology. Regarding cytogenetic lesions, at least, , published here in the JCO in February of 2025 and , posited a new cytogenetic classification system to realize a shared platform upon which we might contextualize those trial results. This article we have here by Dr. Avet-Loiseau, Dr. Munshi, and colleagues, published online in early June of this year and hot off the presses, is the definitive joint statement from the International Myeloma Society (IMS) and the International Myeloma Working Group (IMWG). What is high-risk multiple myeloma for the modern era? The IMS and IMWG Genomics Workshop was held in July 2023 and was attended by international myeloma experts, collaborating to reach consensus based on large volumes of data presented and shared. The datasets included cohorts from the Intergroupe Francophone du Myélome (IFM); the HARMONY project, comprised of multiple European academic trials; the FORTE study, findings from which solidified KRd as a viable induction regimen; the Grupo Español de Mieloma Múltiple (GEM) and the PETHEMA Foundation; the German-Speaking Myeloma Multicenter Group (GMMG); the UK-based Myeloma XI, findings from which confirmed the concept of lenalidomide maintenance; Emory 1000, a large, real-world dataset from Emory University in Atlanta; the Multiple Myeloma Research Foundation Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile (CoMMpass) dataset; and some newly diagnosed myeloma cohorts from the Mayo Clinic. Data were not pooled for analyses and were assessed individually - that is to say, with clear a priori understanding of whence the data had been gathered and for what original purposes. Consensus on topics was developed based on the preponderance of data across studies and cohorts. In terms of results, substantial revisions were made to the genomic staging of high-risk multiple myeloma, and these can be sorted into three major categories: A) alterations to the tumor suppressor gene TP53; B) translocations involving chromosome 14: t(14;16) (c-MAF overexpression), t(14;20) (MAFB overexpression), and t(4;14) (NSD2 overexpression); and C) chromosome 1 abnormalities: deletions of 1p or additional copies of 1q. In terms of category A, TP53 alterations: Deletion of 17p is present in up to 10% of patients at diagnosis and is enriched in relapsed or refractory disease. This is well-documented as a high-risk feature, but the proportion of the myeloma cells with deletion 17p actually impacts prognosis. GEM and HARMONY data analyses confirmed the use of 20% clonal cell fraction as the optimal threshold value for high-risk disease. That is to say, there must be the deletion of 17p in at least 20% of the myeloma cells on a FISH-analysis of a CD138-enriched bone marrow sample to qualify as high-risk disease. TP53 mutations can also occur. Inactivating mutations appear to have deleterious effects similar to chromosomal losses, and the biallelic loss of TP53, however it occurs, portends particularly poor prognosis. This effect is seen across Myeloma XI, CoMMpass, and IFM cohorts. Biallelic loss is rare, it appears to occur in only about 5% of patients, but next-generation sequencing is nevertheless recommended in all myeloma patients. Category B, chromosome 14 translocations: Translocation t(14;16) occurs in about 2% to 3% of patients with newly diagnosed disease. In the available data, primarily real-world IFM data, t(14;16) almost always occurs with chromosome 1 abnormalities. Translocation t(4;14) occurs in about 10% to 12% of newly diagnosed disease, but only patients with specific NSD2 alterations are, in fact, at risk of worse prognosis, which clinically appears to be about one in every three of those patients. And so together, the CoMMpass and Myeloma XI data suggest that translocation t(4;14) only in combination with deletion 1p or gain or amplification of 1q correlates with worse prognosis. Translocation t(14;20) occurs in only 2% of newly diagnosed disease. Similar to translocation t(4;14), it doesn’t appear to have an effect on prognosis, except if the translocation co-occurs with chromosome 1 lesions, in which case patients do fare worse. Overall, these three translocations - t(14;16), t(4;14), and t(14;20) - should be considered high-risk only if chromosome 1 aberrations are also present. In terms of those chromosome 1 aberrations, category C, first deletions of 1p: Occurring in about 13% to 15% of newly diagnosed disease, deletion 1p eliminates critical cell checkpoints and normal apoptotic signaling. In the IFM and CoMMpass dataset analyses, biallelic deletion of 1p and monoallelic deletion of 1p co-occurring with additional copies of 1q denote high-risk. In terms of the other aberration in chromosome 1 possible in myeloma, gain or amplification of 1q: This occurs in up to 35% to 37% of newly diagnosed disease. It upregulates CKS1B, which is a cyclin-dependent kinase, and ANP32E, a histone acetyltransferase inhibitor. GEM and IFM data suggest that gain or amplification of 1q - there was no clear survival detriment to amplification - is best considered as a high-risk feature only in combination with the other risk factors as above. Now, in terms of any other criteria for high-risk disease, there remains one other item, and that has to do with tumor burden. There has been a consensus shift, really, in both the IMS and IMWG to attempt to develop a definition of high-risk disease which is based on biologic features rather than empirically observed and potentially temporally dynamic features, such as lactate dehydrogenase. Beta-2 microglobulin remains an independent high-risk indicator, but care must be taken when measuring it, as renal dysfunction can artificially inflate peripheral titers. The consensus conclusion was that a beta-2 microglobulin of at least 5.5 without renal failure should be considered high-risk but should not preclude detailed genomic profiling. So, in conclusion, the novel 2025 IMS-IMWG risk stratification system for myeloma is binary. It’s either high-risk disease or standard-risk disease. It’s got four criteria. Number one, deletion 17p and/or a TP53 mutation. Clonal cell fraction cut-off, remember, is 20%. Or number two, an IGH translocation - t(4;14), t(14;16), t(14;20) - with 1q gain and/or deletion of 1p. Or a monoallelic deletion of 1p with 1q additional copies or a biallelic deletion of 1p. Or a beta-2 microglobulin of at least 5.5 only when the creatinine is normal. This is a field-defining work that draws on analyses from across the world to put forward a dominant definition of high-risk disease and introduces a new era of biologically informed risk assessment in myeloma. Now, how does this change our clinical approach? FISH must be performed on CD138-enriched samples and should be performed for all patients. Next-generation sequencing should also be performed on all patients. Trials will hopefully now begin to include this novel definition of high-risk multiple myeloma. It does remain to be seen how data from novel therapeutic trials, if stratified according to this novel definition, will be interpreted. Will we find that therapies being evaluated at present have differential effects on myelomas with different genetic lesions? Other unanswered questions also exist. How do we go about integrating this into academic and then community clinical practice? How do we devise public health interventions for low-resource settings? To discuss this piece further, we welcome the esteemed Dr. Nikhil Munshi to the podcast. Dr. Munshi is a world-renowned leader in multiple myeloma and the corresponding author on this paper. As Professor of Medicine at Harvard Medical School, Director of the Multiple Myeloma Effector Cell Therapy Unit, and Director of Basic and Correlative Science at the Jerome Lipper Multiple Myeloma Center of the Dana-Farber Cancer Institute, he has presided over critical discoveries in the field. Thank you for joining us, Dr. Munshi. Dr. Nikhil Munshi: Oh, it’s my pleasure being here, Michael, to discuss this interesting and important publication. Michael Hughes: I had a few questions for you. So number one, this is a comprehensive, shall we say, monumental and wide-ranging definition for high-risk myeloma. How do you hope this will influence or impact the ways we discuss myeloma with patients in the exam room? And how do we make some of these components recommended, in particular next-generation sequencing, feasible in lower-resource settings? Dr. Nikhil Munshi: So those are two very important questions. Let’s start with the first: How do we utilize this in our day-to-day patient care setting? So, as you know well, we have always tried to identify those patients who do not do so well with the current existing treatment. And for the last 30 years, what constitutes a myeloma of higher risk has continued to change with improvement in our treatment. The current definition basically centers around a quarter of the patients whose PFS is less than 2 to 3 years. And those would require some more involved therapeutic management. So that was a starting point of defining patients and the features. As we developed this consensus amongst ourselves - and it’s titled as “International Myeloma Society, International Myeloma Working Group Consensus Recommendation” - this IMS-IMWG type of recommendation we have done for many years, improvising in various areas of myeloma care. Now, here, we looked at the data that was existing all across the globe, utilizing newer treatment and trying to identify that with these four-drug regimens, with transplant and some of the immunotherapy, which group of patients do not do as well. And this is where this current algorithm comes up. So before I answer your question straight, “How do we use it?” I might like to just suggest, “What are those features that we have identified?” There are four features which constitute high-risk disease in the newer definition. Those with deletion 17p with 20% clonality and/or TP53 mutation. Number two, patients with one of the translocations - t(4;14), t(14;16), or t(14;20) - co-occurring with 1q amplification or deletion 1p32. And that’s a change. Previously, just the translocation was considered high-risk. Now we need a co-occurrence for it to be called high-risk. The third group is patients having biallelic deletion 1p32 or monoallelic deletion 1p32 along with 1q amplification. And finally, patients with high beta-2 microglobulin, more than or equal to 5.5 mg/dL, with normal creatinine less than 1.2 mg/dL. And the question, “How do we use this?” There are multiple areas where we incorporate high-risk features in our treatment algorithm. One of the first areas is where we would consider the induction regimen. If a patient has a high-risk disease, we would definitely consider a four-drug regimen rather than a three-drug regimen, although we are beginning to incorporate four-drug for all groups. That’s one important thing. Number two, those are the patients where we do consider consolidation with transplant or maybe in the new world, considering some of the immunotherapeutic consolidation more early or more aggressively. Number three, these are the patients who get a little bit more maintenance therapy. So normally, lenalidomide might end up being our standard maintenance regimen. In patients who have high-risk disease, we incorporate either addition of daratumumab or the anti-CD38 targeting antibody and/or addition of proteasome inhibitor, either bortezomib or carfilzomib. So you would have multi-drug maintenance therapy in these patients. And in high-risk patients, we follow them with maintenance longer periods of time. One very critically important point to keep in mind is that to get the better outcome in high-risk disease, we must try to get them into MRD negativity because there is clear data that patients who do achieve MRD negativity, despite having high-risk disease, have a much superior outcome. They become near to standard-risk disease. And so, in high-risk patients, I would try to do whatever various options I have to try and get them into MRD-negative status. And when these patients relapse, we do not wait for the classic progression criteria to be met before we intervene. We would propose and suggest that we intervene earlier before the disease really blasts off. And so there are a number of areas in our setting where this high-risk definition will help us intervene appropriately and also with appropriate aggressiveness to achieve better outcome, to make this similar to standard-risk disease. Michael Hughes: Thank you, Dr. Munshi. And thoughts on how to really integrate this not only into academic centers but also lower-resource settings? Dr. Nikhil Munshi: So that’s a very important question, Michael. And when we were developing this consensus, we were very cognizant of that fact. So wherever available, I think we are recommending that over a period of next 2, 3, 5 years, we should begin to switch over to sequencing-based methods because two components of this definition, one is TP53 mutation, which we cannot do without sequencing, and also reliably detecting deletion 1p requires sequencing-based method. So in the low-resource countries - and there are many in this world, and also even in our own country, patients may not be able to afford it - the older method with FISH or similar such technology, which is more affordable, is also acceptable for current time. They may miss a very small number of patients, maybe 2% to 3%, where these finer changes are not picked up, but a majority of this would be captured by them. So the current practice might still be applicable with some limitation in those patient populations, and that’s what we would recommend. What is happening, fortunately, is that actually sequencing-based method is becoming cheaper. And in many centers, it is cheaper to do the sequencing rather than to do the FISH analysis. And so my hope is that even in low-resource centers, sequencing might be more economical in the end. It’s, I think, the access to technology, which is a little bit limited currently, but it’s hopefully becoming available soon. Michael Hughes: Thank you, Dr. Munshi. And staying for a minute and looking at the multiple myeloma subsets which might be missed by this really still very broad-ranging high-risk definition, at least by prior risk stratification systems, right, there is this group of patients who have standard-risk cytogenetics by R-ISS or R2-ISS, but they have primary refractory disease or they relapse early. We call these, as you are well aware, functionally high-risk disease. What proportion of previously FHR, functionally high-risk, myeloma patients do you expect to be captured by this novel definition? Dr. Nikhil Munshi: So I think the newer definition - and we can look at it both ways, but the newer definition should capture most of the functionally high-risk definition. To put it differently, Michael, there are patients who we know are, as you mentioned, functionally high-risk. Those are the patients who might have plasma cell leukemia, those who might have extramedullary disease, those who might not respond to our four-drug induction. If you don’t respond to the four-drug induction, almost by definition, they are high-risk. However, a majority of them have one of the abnormalities that we are describing here. There would be a very small proportion which may not have. And if they do not have, we know one of the important components of this definition here is also that the genome, we know, keeps on evolving. So there may be a very small clone with the high-risk feature which was not obvious in the beginning. Following treatments or following relapse, that clone predominates, and now the patient’s disease becomes high-risk. So the definition would incorporate or would capture these functional high-risk patients, but as you said, in countries where resources are not available, using this functional high-risk would also be helpful and advantageous. Sometimes LDH ends up being a high-risk. In our studies, LDH has not come out to be high-risk anymore because the features we are describing captures most of those patients, but those alternatives, older, can still be considered if other newer techniques are not available. Michael Hughes: Got you. And in terms of these older definitions, yes, that incorporate tumor burden, these empirical observations about how myeloma presents, do you foresee any additional tumor burden indicators being added to future definitions of high-risk disease? Or do you instead see this particular definition as a major waypoint on the journey towards a fully biologically grounded definition of high-risk disease? Dr. Nikhil Munshi: I think your second part is what is going to happen. I think the tumor burden-related definition is being now replaced by the biological or genomic-based definition. And I think at some point, it will be quite fully replaced. One component not here, and it is because one thing, we don’t have enough data; number two, we don’t know how it will pan out, is also the influence of the microenvironment on the risk definition. For example, the immune system, the immune function, etc. But not enough data exists to suggest how it would change the current definition. So in future, would a definition be totally genomic or it could be more integrative? And my personal guess is that it would be more integrative and that some immune features might come into the picture, especially now that we are using immune-based therapy as a very important component of treatment - CAR T-cells, bispecific, and antibody-based treatments. What role the immune system plays in either supporting tumor or what role suppression of the anti-tumor immunity plays? They all will be important how patient outcomes end up being, and which in turn could translate into how patient’s risk stratification might happen. So I think the older tumor burden-related definitions probably will become things of the past. What we have currently proposed and consensus developed is the new path forward, and... /episode/index/show/jcopodcast/id/37576385

JCO Article Insights: Pooled Taletrectinib Efficacy and Safety 06/30/2025

JCO Article Insights: Pooled Taletrectinib Efficacy and Safety In this JCO Article Insights episode, host Peter Li summarizes "" by Pérol et al, published April 03, 2025, followed by an interview with first author, Dr Maurice Pérol. TRANSCRIPT The disclosures for guests on this podcast can be found in the show notes. Dr. Peter Li: Welcome to this episode of . I am Dr. Peter Li, JCO’s editorial fellow, and today I am joined by Dr. Maurice Pérol on “,” by Pérol et al. At the time of this recording, our guest has disclosures that will be linked in the transcript. Before we start our interview, I want to give our listeners a quick summary of the TRUST study. For those tuning in, the TRUST study is a phase II, single-arm, open-label, nonrandomized, multicenter trial looking at the efficacy and safety of a novel, next-generation ROS1 TKI, taletrectinib, in advanced ROS1-mutated non–small cell lung cancer. While a relatively rare mutation, the prevalence of ROS1 mutations ranges from 0.9% to 2.6% of patients, with a third of patients presenting with brain mets at diagnosis.Current FDA-approved therapies include crizotinib, entrectinib, and repotrectinib, which have varying degrees of efficacy, in-coming with trade-offs in CNS penetrance and safety with newer generations, particularly in the realm of neurological side effects, highlighting an unmet need in this arena. A total of 273 patients with advanced non–small cell lung cancer with confirmed ROS1 mutation were recruited for this study. 160 patients were TKI-naive, while 113 were TKI-experienced with either crizotinib or entrectinib. Patients with asymptomatic brain mets were also allowed to enroll. In the TKI-naive arm, the median age was 57, with 91% of patients having stage IV disease, 20% having no more than one cycle of chemo, and 23% having brain mets at baseline. In the TKI-experienced arm, the median age was 53, with 97% having stage IV disease, 37% having received prior chemo, and about 50% having brain mets. Furthermore, about 10% of the study population had received entrectinib, while more than 90% had received crizotinib. About 10% had a known G2032R acquired resistance mutation. Taletrectinib was dosed at 600 mg daily until disease progression or unacceptable toxicities. The primary endpoint was overall response rate, with secondary endpoints being disease control rate, duration of response, time to response, and progression-free survival. For those with brain mets, intracranial overall response rate and disease control rate were also assessed. Median follow-up time was about 21 months in both cohorts. In the TKI-naive cohort, the overall response rate was 89%, with 8 patients achieving a complete response. Disease control rate was 95%, with a median duration of response of 44.2 months. Time to treatment response was about 1.5 months. Median progression-free survival was 45.6 months, with 52.6% not having progressed at 3 years. While overall survival data were immature, 66% of patients were still alive at 3 years. In the pretreated cohort, overall response rate was 56%, with 5 patients achieving a complete response. Overall response rate was 53% for those who were crizotinib-pretreated and 80% for the entrectinib-pretreated patients. Disease control rate was 88%, and median duration of response was about 16.5 months. Time to treatment response was also 1.5 months, and median progression-free survival was 9.7 months. Median overall survival was not reached, but 77.5% of patients were still alive at 1 year. Responses were consistently seen across subgroup analyses. 17 TKI-naive and 32 TKI-pretreated patients had measurable brain mets. In the TKI-naive arm, intracranial overall response rate was 77%. Disease control rate was 88%, and duration of response was 15 months. In the TKI-pretreated arm, intracranial overall response was 66%, with one patient achieving complete response. The disease control rate was 94%, and duration of response was about a year. For the 13 patients who had a known G2032R mutation, a 62% response rate was noted. Most common treatment-related side effects were AST/ALT elevation, nausea, and vomiting, with most being grade 1 or 2. Most common neurological side effects were dizziness, dysgeusia, and headache. Again, most were grade 1. QTc prolongation is another important adverse event to note, occurring in about 18% of all patients. Discontinuation rate from treatment was only 7%. There were three treatment-related deaths in this study: one from hepatic failure, one from pneumonia in the naive arm, and one from liver dysfunction in the pretreated arm. Dr. Peter Li: Maurice, thank you so much for joining us today to talk about your paper. Would you mind just giving yourself a brief introduction to the listeners out there of who you are? Dr. Maurice Pérol: So, my name is Maurice Perol. I'm a thoracic oncologist working in the Cancer Center of Lyon in France. And I'm involved in clinical research in thoracic oncology. I've been involved for many years now. Dr. Peter Li: Okay. And for listeners out there, don't forget, he's also the primary author of the paper that we just talked about. So, Maurice, let's begin. Can you tell our listeners what is the significance of your study? Dr. Maurice Pérol: Well, the results of these two large phase II studies - TRUST-I, which has been conducted in China, and TRUST-II, which was a global, worldwide phase II study - so, the results place taletrectinib as the TKI with the most favorable efficacy-tolerability ratio of the available ROS1-targeting TKIs, especially in frontline therapy. And this is based on the response rate, which was very impressive, the CNS penetration with a great CNS activity, the duration of response with a compelling 45 months median PFS in frontline setting. The level of activity in pretreated patients after crizotinib or entrectinib was also impressive and similar to that of repotrectinib, for example, but with a more favorable neurological tolerance profile. The toxicity is mainly represented with grade 1 or 2 transaminase elevation, but without clinical symptoms, and GI toxicity, but mainly grade 1 and 2. The neurological toxicity is low, especially for dizziness, showing that taletrectinib spares TrKB in a large part. And finally, there is also a decrease in toxicity over time, especially for GI toxicity and liver toxicities, which allows a very long and a prolonged administration, which is very important in this setting. Dr. Peter Li: These are all excellent points. Can you tell the listeners if there are any limitations that we should be concerned about, about this study? Dr. Maurice Pérol: Sure. This data comes from single-arm phase II studies. So, this is not comparative data. And a phase III trial, which compares taletrectinib to crizotinib, is ongoing to evaluate the superiority of taletrectinib over the standard of care. Another limitation comes from the lack of systematic brain imaging at each tumor evaluation in patients without brain metastases at baseline, not allowing to assess the intracranial PFS in all patients, and which did not allow us to assess the CNS protective issue from taletrectinib, especially in patients without brain metastases at baseline. Dr. Peter Li: Another question that I have is, with this novel TKI now available, how would you recommend the sequencing of these drugs? Would you start with someone on an alternate TKI and then reserve taletrectinib second line or later? Or would you use it upfront? Or does it depend? Dr. Maurice Pérol: Well, it is a very important question, as we have now different available TKIs. Looking at the efficacy-toxicity balance, I would strongly favor the use of taletrectinib in frontline setting, in first line. The response rate, the CNS activity, the duration of response with a very compelling 45 months median PFS, and moreover, the good tolerance profile over time are strong arguments in favor of giving taletrectinib in frontline. Generally speaking, the use of the most active agent as frontline treatment in lung cancer depending on an oncogenic addiction is probably the best way to improve the patient's outcome. This is true for patients with EGFR mutation, for patients with ALK fusions, and this is probably also true for patients with ROS1 fusion. So, I would probably argue in favor of a frontline use of taletrectinib. Dr. Peter Li: Listeners are going to ask, well, if you use taletrectinib upfront, then what are you going to use second line once they progress? Dr. Maurice Pérol: Well, we have some new compounds which are under development today. For example, the NVL-520, which is a very interesting compound, which seems also to be active in case of resistance mutation. But I do think that we have to use the best-in-class TKI in frontline because, you know, the extension of PFS after acquired resistance you can obtain with a second-line TKI is always shorter than the benefit you can obtain by using the most active agent in frontline. And this is true for the majority of oncogenic addiction in lung cancer. Dr. Peter Li: That makes sense. I also noticed that cognitive impairment wasn't listed in the safety table. Is that not an issue that you've observed at all with taletrectinib, or is it still an issue but less so because, like you mentioned earlier, because of its higher selectivity? Dr. Maurice Pérol: Well, this is a good question because we have some ROS1-targeting TKIs like repotrectinib, entrectinib, and even lorlatinib, with some neurological adverse events and some cognitive issues. Taletrectinib is a very selective ROS1-targeting TKI, and it spares very well the TrKB, for example, explaining that we did not observe any cognitive impairment with taletrectinib in the TRUST study, showing also with the low level of other neurological adverse events, dizziness, dysgeusia, for example, the high selectivity of the compound and the preservation of TrKB. So, this is very important when you consider the long duration of treatment in those patients with ROS1 fusion. If you have to take a drug for more than 2, 3, or 4 years, of course, the neurological adverse events are very important, and they can clearly impair the quality of life. So, this is a very important point, the very low level of neurological toxicity of taletrectinib. Dr. Peter Li: And I think that goes to say why you would favor using it frontline as well compared to entrectinib or repotrectinib. Last question that we have for you is: well, what's next? You mentioned there's a phase III trial comparing it to crizotinib. I think one of the questions that a lot of us would have is: why not compare it to one of the newer agents as a comparator arm? Dr. Maurice Pérol: Well, this is a good question. Crizotinib remains the standard of care in many countries for ROS1-positive advanced non–small cell lung cancer outside of the US, especially in Europe, and in particular in patients who do not have brain metastases at diagnosis. Entrectinib has a better CNS penetration, but it did not achieve a better PFS than crizotinib in phase I/II trials, and clearly, it has a less favorable tolerance profile with weight gain, edema, and neurological adverse events. Repotrectinib has overall a level of activity which seems close to that of taletrectinib. So, it makes it difficult to consider a comparative trial that would, for example, test taletrectinib in comparison with repotrectinib because this kind of study would need a very large number of patients and a very late readout. Considering if you have a median PFS of more than 3 or 4 years, it would be very difficult to have results in before 4-5 years. So, from a pragmatic point of view, the comparison of taletrectinib to crizotinib is probably the best way to evaluate in a phase III setting the level of activity of taletrectinib, especially in the CNS, because this study will probably allow us to assess the CNS protective effect of the compound for patients without brain metastates at baseline. So, I think probably it's a pragmatic study that will allow us to confirm the high level of activity and the good tolerance profile of taletrectinib. Dr. Peter Li: Well, thank you, Maurice, so much for speaking about the JCO article, “Taletrectinib in ROS1-Mutated Non–Small Cell Lung Cancer: TRUST,” and for all your valuable input today. Thank you for listening to Please come back for more interviews and article summaries, and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit . The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. /episode/index/show/jcopodcast/id/37178720

JCO at ASCO Annual Meeting: Neoadjuvant Osimertinib for Resectable EGFR-Mutated NSCLC 06/02/2025

JCO at ASCO Annual Meeting: Neoadjuvant Osimertinib for Resectable EGFR-Mutated NSCLC JCO Editorial Fellow Dr. Ece Cali Daylan and JCO Associate Editor Dr. Thomas Stinchcombe discuss the ASCO 2025 Simultaneous Publication paper "." Transcript The guest on this podcast episode has no disclosures to declare. Dr. Ece Cali: Hello, and welcome to our 2025 ASCO Annual Meeting series, where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's meeting. I'm your host, Dr. Ece Cali, JCO Editorial Fellow, and I am joined by JCO Associate Editor, Dr. Tom Stinchcombe. In this episode, we will discuss the Journal of Clinical Oncology article and abstract presentation ".” NeoADAURA is a randomized global phase III study investigating the efficacy of neoadjuvant osimertinib-containing regimens in patients with resectable EGFR-mutated stage II to IIIB non–small-cell lung cancer. 358 patients were randomized 1:1:1 to receive osimertinib plus chemotherapy, osimertinib monotherapy, or placebo plus chemotherapy in the neoadjuvant setting. The primary endpoint was major pathological response. Osimertinib plus chemotherapy and osimertinib alone demonstrated MPR rates of 26% and 25%, respectively, compared to 2% in the chemotherapy plus placebo arm with a p-value of less than 0.001. Tom, can you please explain to our listeners how you interpret this data? Dr. Thomas Stinchcombe: Great question. Yeah, I think to give a little context, obviously, chemotherapy and immunotherapies preoperatively is becoming the standard of care. However, patients with EGFR-mutant lung cancer generally have not responded to immunotherapy, and many of the trials excluded patients with known EGFR mutation. There have been smaller phase II trials that had looked at EGFR TKIs preoperatively, but none of these were definitive. So I think that this trial is a big trial, and I think some of the strengths are that it has osimertinib alone and chemotherapy with osimertinib arms as compared to the standard of chemotherapy. I think it's going to be really interesting at the meeting to see how this is discussed by the discussant and also what the reaction is to its public presentation. And I think that's largely because there's an alternative paradigm now, surgical resection adjuvant osimertinib, that's available to patients. So I think this will be interesting to see what the reaction is to the induction therapy. For patients with known N2 disease, I've generally given some form of induction therapy prior to surgical resection. So I think that's the subgroup of patients that I'm most likely to employ this approach with based on the results. Dr. Ece Cali: So, in this trial, more than 90% of the patients on the osimertinib-containing regimens underwent curative-intent surgery. So, this speaks to the feasibility of the approach, and the higher MPR rate with osimertinib-containing regimens is encouraging. Event-free survival data is currently immature. You have already touched upon some of the strengths of the trial, but what are the weaknesses and the strengths of this trial? Dr. Thomas Stinchcombe: So, I mean, I think there are some weaknesses. A major pathological response was chosen as an endpoint, and there could be an argument that path CR is more of a prognostic marker. However, the rates of path CR are relatively low, so it would have been very hard to design a trial such as that. And then I think the trial started off as a preoperative trial but effectively became a perioperative trial with preoperative EGFR-TKI, postoperative osimertinib. And so I think it's going to be very hard to determine what the contribution of the components are. And then you've hit on another part that I think is very important when we interpret the data that the maturity on the event-free survival is only 15%, and most people are still on therapy. So the event-free survival, which is an important endpoint, is very immature right now. Dr. Ece Cali: And this trial was designed to compare the neoadjuvant approaches, hence the comparator arm here is neoadjuvant chemotherapy followed by surgery. So, considering the ADAURA trial results with upfront surgery followed by osimertinib as adjuvant, so how do you see this trial's impact on the current clinical practice? Dr. Thomas Stinchcombe: Well, very good question, I think one that we're still struggling with as we kind of look at this data. I think, for me, stage II patients will most likely go to surgery and then get adjuvant osimertinib, and then maybe the N2 patients will get an osimertinib-containing regimen as an induction therapy. I think one of the questions is does it really matter when you get the osimertinib as long as you get it at some point? And I think that's going to be the critical interpretation of some of the data at this point. Dr. Ece Cali: And how do you think this trial shapes the future research for patients with resectable EGFR-mutated lung cancer? Dr. Thomas Stinchcombe: Well, I mean, I think it shows that chemotherapy was really modestly active with an MPR rate of 2%, no pathological responses. And then I think you're going to have to look at an osimertinib plus another targeted therapy component. I think, you know, when I looked at the osimertinib versus the chemo-osimertinib arm, I also was sort of surprised that the MPR rate and the path CR rate were very, very similar. So I think that the question is would a double targeted therapy approach or some other approach matter? And I think it also sets a safety standard. And you touched on this in your comments, that there was not a disparity in terms of the rate of going to surgery or R0/R1 resections. So patients were not having progressive disease events or toxicities that prevented surgery. So I think it does give us good safety data. Dr. Ece Cali: Tom, thank you so much for sharing your insights on the JCO article, "Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non–Small-Cell Lung Cancer." Join us again for the latest simultaneous publications from the 2025 ASCO Annual Meeting, and please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of ASCO 2025. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. /episode/index/show/jcopodcast/id/36806655

JCO at ASCO Annual Meeting: Use of Low-Value Cancer Treatments in Medicare 05/31/2025

JCO at ASCO Annual Meeting: Use of Low-Value Cancer Treatments in Medicare JCO Editorial Fellow Dr. Lauren Shih and JCO Associate Editor Dr. Stephanie Wheeler discuss the ASCO 25 Simultaneous Publication paper "Use of Low-Value Cancer Treatments in Medicare Advantage Versus Traditional Medicare." Transcript The guest on this podcast episode has no disclosures to declare. Dr. Lauren Shih: Hello, and welcome to our 2025 ASCO annual meeting series where we cover some of the top JCO papers published simultaneously with their abstract presentations at this year's meeting. I'm your host, Dr. Lauren Shih, JCO editorial fellow, and I'm joined by JCO Associate Editor Dr. Stephanie Wheeler to discuss the Journal of Clinical Oncology article and abstract presentation "." Let's start with the relevance of the article. Dr. Wheeler, can you explain this to our listeners? Dr. Stephanie Wheeler: Thank you so much. Let's get right into it. So this article is really about understanding different types of Medicare plans and what we should expect to see in terms of their use of low-value treatments for cancer patients. So, as Medicare really is focused on trying to limit the use of low-value cancer treatments, we really need to better understand the drivers of variability. So we know that many cancer patients have multiple treatment options available to them. We also know that the vast majority of older adults beyond age 65 are insured by Medicare, and about half of them are on Medicare Advantage plans, which are serviced by private insurance. And private insurance companies in this case are receiving capitated payments for Medicare beneficiaries to manage their service utilization and reduce costs. So, with respect to Medicare Advantage versus the traditional fee-for-service Medicare, it's not really been known to what extent low-value treatments are differentially used by these types of plans for cancer patients. And so that was really the focus of this article. What the authors found is that across six different types of treatments, in general, the folks who were enrolled in Medicare Advantage plans had reduced use of low-value treatment. So that's a good sign for Medicare beneficiaries. And although the relative difference in that use was somewhat low, this translates to a significant number of Medicare enrollees across the country not receiving these low-value treatments. And of course, this translates to considerable savings at the society level. Dr. Lauren Shih: Are there any additional key results that we should review? Dr. Stephanie Wheeler: Yeah. So I'll tell you just a little bit more about the methods and also their findings. So they looked at six different low-value treatments, and this was in, again, 100% of national Medicare enrollees from 2015 through 2021. So the six low-value treatments that they examined were the use of G-CSFs among patients receiving low-risk chemotherapy and denosumab for those who had castration-sensitive prostate cancer. Then they also looked at four high-cost treatments, including using nab-paclitaxel instead of paclitaxel for patients with breast or lung cancer; second, adding bevacizumab to carboplatin plus paclitaxel for ovarian cancer; third, using brand-name drugs instead of generics when generics were available; and fourth, using biologics instead of biosimilars when biosimilars were available. And these are all, by the way, non-recommended treatments according to a variety of guidelines, including NCCN and ASCO's Choosing Wisely guidelines. So they used the Medicare claims data to examine use of these regimens. They also analyzed results by type of Medicare Advantage plan, whether people were enrolled in a health maintenance organization plan, or an HMO, or a preferred provider organization plan, or a PPO. They also looked at the largest Medicare Advantage insurers—including Aetna, Blue Cross Blue Shield, Cigna, Humana, and UnitedHealth—and limited their analyses to those that had complete encounter data. And what they found across the board is that the enrollees in Medicare Advantage plans generally had lower use of these low-value treatments. And the largest differences between Medicare Advantage and traditional Medicare plans were in the outcomes, including G-CSF use and using denosumab for castration-resistant prostate cancer, and then the combination of bevacizumab, carboplatin, and paclitaxel versus carboplatin and paclitaxel. And all of these had a change in use ranging from about 19% change to 24% change in use. This is significant as a field as we look at ways in which different plan organization can influence use of treatments, particularly given the excess cost of cancer care. This is something we really want to pay attention to. So I'd encourage folks to look more closely at the results by treatment type as well as the results by plan type to see a little bit more about what was going on across different plan types. Dr. Lauren Shih: Great. And are there any outstanding questions that need to be answered? Dr. Stephanie Wheeler: Yes, there always are, of course. I think the study has several strengths that are worth noting. First, they have 100% of Medicare enrollees, so there's national coverage there, which is, you know, quite outstanding. They also use an appropriate choice of analysis to help deal with some of the selection. So they use inverse probability of treatment weights, and they control for practice and county indicators to try to get some realistic adjustment for the selection that happens in terms of how patients are enrolled in different Medicare Advantage versus traditional fee-for-Medicare plans. These statistical approaches are a good idea, but they are limited by the observed variables that we can use for these kinds of adjustments. And so any unobserved—confounding or any unobserved factors that would influence selection in these plans aren't going to be captured well. So preferences, for example, that patients may have about different types of plans when they're insuring themselves and their families may not be captured. Second, the data that are used are only encounter data from those plans with complete records. That may mean that smaller Medicare Advantage insurers or those that don't have as comprehensive records are not included. So this may not be reflective of their practice patterns. And then third, of course, this only looked at six different low-value cancer treatments. It remains to be seen whether this kind of finding extends to other types of low-value cancer treatments, and that's an opportunity for future study. Finally, I would say that we don't exactly know why these patterns exist. It could be that Medicare Advantage plans have different approaches to prior authorization. They could have more in-house quality control and management to really understand, among their population for whom they're receiving Medicare Advantage payments, to really look at care quality and assess Choosing Wisely guidelines. We don't know exactly how that's playing out. And so we need additional data to really figure out what's working here and what are opportunities for future policy and payment innovations that can further reduce low-value care. Dr. Lauren Shih: Great. Thank you so much, Dr. Wheeler, for speaking to us about the JCO article, "Use of Low-Value Cancer Treatments in Medicare Advantage Versus Traditional Medicare." We really appreciate your insights. Dr. Stephanie Wheeler: Thanks for having me. Dr. Lauren Shih: Join us again for the latest simultaneous publications from the ASCO 2025 Annual Meeting. Please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of ASCO 2025. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. /episode/index/show/jcopodcast/id/36770800

JCO at ASCO Annual Meeting: Avelumab Plus Cetuximab vs. Avelumab in Advanced cSCC 05/31/2025

JCO at ASCO Annual Meeting: Avelumab Plus Cetuximab vs. Avelumab in Advanced cSCC JCO Editorial Fellow Dr. Ece Cali Daylan and JCO Associate Editor Dr. Grant McArthur discuss the ASCO 2025 Simultaneous Publication paper "." Transcript The guest on this podcast episode has no disclosures to declare. Dr. Ece Cali: Hello, and welcome to our 2025 ASCO Annual Meeting series where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's meeting. I'm your host, Dr. Ece Cali, and I'm joined by JCO Associate Editor Dr. Grant McArthur. Today, we will discuss Journal of Clinical Oncology article and abstract presentation "." Let's start with a brief overview of the clinical trial. This is a randomized phase II trial that compared avelumab plus cetuximab to avelumab in PD-1/PD-L1 antibody-naive patients with advanced cutaneous squamous cell carcinoma. This is a cooperative group study conducted in the United States. Sixty patients were randomized one-to-one and stratified by PD-L1 and HIV status. The primary endpoint was progression-free survival. Patients on the cetuximab plus avelumab arm had a median PFS of 11.1 months, while patients on the avelumab arm had a median PFS of 3 months, corresponding to a hazard ratio of 0.48 with a p-value of 0.018. Grade III or higher treatment-related adverse events occurred in 48% of the patients on the combination arm versus 21% of patients on the avelumab arm. Dr. McArthur, can you please explain to our listeners how you interpret this data? Dr. Grant McArthur: These results are very important because they provide proof of concept for inhibiting PD-L1 as a target when combined with EGFR, so inhibiting PD-L1 with avelumab and inhibiting EGFR with cetuximab, in a randomized trial with a very significant impact in terms of efficacy. So, what this does is it provides proof of concept for inhibiting those targets in cutaneous squamous cell carcinoma of the skin. Avelumab is not approved for cutaneous squamous cell carcinoma of the skin, and so further studies would need to be done, particularly asking the question about combination with the approved PD-1 agents cemiplimab and pembrolizumab. Dr. Ece Cali: I still find the difference in median PFS with various PD-1/PD-L1 inhibitors striking in this context. In this trial, avelumab, as you mentioned, the PD-L1 inhibitor, demonstrated a median PFS of 3 months, whereas PD-1 inhibitors cemiplimab and pembrolizumab have demonstrated longer median PFS in other trials. So, what are some potential reasons for this, and do you think this difference impacts the interpretation of the results here? Dr. Grant McArthur: So, the obvious reason for the differences is that avelumab targets PD-L1, where pembrolizumab and cemiplimab inhibit PD-1, so there could be simply a difference in the target to explain those differences in progression-free survival. However, as you point out, cross-trial comparisons, one has to do with caution because you can, in different phase II studies, enroll different patient populations, which would impact the progression-free survival. So, we have to be cautious about that interpretation. However, given that cemiplimab and pembrolizumab are the approved agents, I think they are the logical ones for further clinical development. Nonetheless, this is still a very important proof-of-concept trial showing that there is a strong clinical signal when you combine EGFR inhibition with inhibition of PD-L1 versus PD-L1 alone. Dr. Ece Cali: I want to highlight some of the safety data presented in this trial as well. The treatment discontinuation rate due to adverse events was much higher in the combination arm, reaching 31% compared to the 14% in the single-agent avelumab arm. The most common grade III adverse events were infusion reaction, rash, and diarrhea in the combination arm. So, these adverse events may affect patients' quality of life significantly. So, what are your thoughts on this, Dr. McArthur? Dr. Grant McArthur: So, the safety data is important. What we're seeing is safety related to each individual agent. So, we have diarrhea and skin rash from the cetuximab, and the infusion reactions is a common toxicity of avelumab. I think what's important, given this is proof of concept inhibiting these targets going forward to further studies, is that agents such as cemiplimab and pembrolizumab have a very low infusion reaction rate. So, the treatment discontinuations due to infusion reaction are unlikely to be an issue with cemiplimab and pembrolizumab when further clinical trials are done. Of course, there is still the issue of diarrhea and skin rash. Now, that can be managed in many patients with EGFR inhibition, you know. However, one would have to await safety data from a significant patient cohort with a combination of cetuximab with either cemiplimab or pembrolizumab, of course, to assess the clinical impact of those safety signals. But I would expect there to be definitely rash and diarrhea as predominant toxicities with those other combinations as well. Dr. Ece Cali: And lastly, I think we touched upon this a little bit, but how do you think this trial impacts the clinical practice, and what are some outstanding questions that need to be addressed in this field in light of the data from this trial? Dr. Grant McArthur: So, the most important outstanding question is - of course, we've already alluded to in our conversation - regarding using anti-PD-1 agents such as pembrolizumab or cemiplimab. So, that needs to be undertaken. Clearly, a randomized trial would be required combining cetuximab with those agents because they are quite active as single agents with impressive response rates and PFS. So, that is the way forward. There's other important clinical questions as well, though. So, patients that get locally aggressive or metastatic cutaneous squamous cell carcinoma of the skin are often immunosuppressed. And so, we do need data in patients that are immunosuppressed, either due to treatment of immune-related disorders - and also organ transplantation. We see a lot of cutaneous squamous cell carcinoma in organ transplant patients. So, these are important patient subsets that would also need to be investigated in further clinical development. However, overall, you know, this is a strong signal, hazard ratio of less than 0.5, and very worthy of further investigation in randomized trials of inhibiting these targets. Dr. Ece Cali: This was a great discussion. Thank you so much for your insight, Dr. McArthur, for speaking about the JCO article "A Phase II Randomized Trial of Avelumab Plus Cetuximab Versus Avelumab Alone in Advanced Cutaneous Squamous Cell Carcinoma." Join us again for the latest simultaneous publications from the 2025 ASCO Annual Meeting. Please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of ASCO 2025. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. /episode/index/show/jcopodcast/id/36770985

JCO at ASCO Annual Meeting: TTFields in Locally Advanced Pancreatic Adenocarcinoma 05/31/2025

JCO at ASCO Annual Meeting: TTFields in Locally Advanced Pancreatic Adenocarcinoma JCO Editorial Fellow Peter Li and JCO Associate Editor Eileen O'Reilly discuss the ASCO 25 Simultaneous Publication paper "." Transcript The guest on this podcast episode has no disclosures to declare. Dr. Peter Li: Hello, and welcome to our 2025 ASCO Annual Meeting series, where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's meeting. I'm your host, Dr. Peter Li, and I'm joined by JCO Associate Editor Dr. Eileen O'Reilly to discuss the Journal of Clinical Oncology article and abstract presentation "." Now, let's start with the relevance of the article. Eileen, can you explain this study to our listeners? Dr. Eileen O'Reilly: Thanks very much, Peter, for the invitation today to discuss this. Yes, so this is a positive phase 3 trial that was conducted in locally advanced, unresectable pancreas cancer. Patients were randomized to receive either gemcitabine and nab-paclitaxel, international standard, with or without tumor-treating fields. And this is a device like a battery pack that you would wear with a goal to wear that approximately 18 hours a day. And the primary endpoint of this study was overall survival, with key secondary endpoints of tumor response, progression-free survival, looking at pain-free survival, and distant progression-free survival. So, the primary endpoint was met with a median overall survival of 16.2 months compared to 14.2 months on the intervention versus control arm, with a hazard ratio of 0.82. And so that met the pre-specified boundary. There was not an increase in progression-free survival, but there was an increase in control of pain on the tumor-treating fields study. So, it was a large, global study, community, academic sites, randomized 570 people, and it supports what I think we've seen in other difficult-to-treat malignancies using tumor-treating fields, that there's a signal of interest. Dr. Peter Li: Can you speak to some of the strengths and weaknesses of this study? Dr. Eileen O'Reilly: So, strengths: it was a large study. It included community sites, it included academic sites. It included ECOG performance status 0, 1, and some patients with 2. The intent was locally advanced. It probably is fair to say that there were some patients who had more advanced disease based on early progression, based on relatively high CA 19-9 for a percentage of people. But likely that was, with random assignment, that would have presumably fallen out between the arms. The inclusion of patients with a lower performance status is nice to see in large phase 3 studies in pancreas cancer. So, they would be some of the strengths. So maybe some of the limitations are the fact that it's an open-label study - so, always some biases inherent in that. Acknowledging that the primary endpoint was overall survival, presumably that wouldn't be directly influenced by that. And there was an imbalance of women on the control arm, and women do fare a little better in this disease, so possibly kind of weighted one of the study arms a little bit. But nonetheless, I think it was a rigorously designed and rigorously conducted phase 3 trial. It's always hard to fully interpret the signal in locally advanced disease because of the fact that some patients go on to surgery, some patients have a treatment switch of cytotoxic therapy, some patients will go on to radiation. And the endpoint here of overall survival, to a degree, eliminates some of that. So, the benchmark, I think, was generally high here. Dr. Peter Li: Gotcha. And then with these findings and this positive study, how do you foresee this research being implemented and how it will impact clinical practice moving forward? Dr. Eileen O'Reilly: I think there'll be an educational need to introduce this approach to the community and to the pancreas cancer world. Again, there's a precedent in glioblastoma and data from other diseases, so there's some familiarity with this. I think people always want to understand how it works and why it works, and that's something that we'll look forward to hearing more about mechanistically, and also seeing how it can be built upon. And there's some intriguing data with the combination of tumor-treating fields and immunotherapy that's being evaluated in the PANOVA-4 study. So, we'll stay tuned to hear how that reads out in due course. But I think overall, it'll be educational and learning, managing the cutaneous impacts or some skin irritation effects from this, and building on this signal in locally advanced disease. Dr. Peter Li: Well, thank you so much, Eileen, for your time and for speaking about the JCO article, "Tumor Treating Fields with Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma: Randomized, Open-Label, Pivotal, Phase 3 PANOVA-3 Study." Join us again for the latest simultaneous publications from the 2025 ASCO Annual Meeting. Please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of ASCO 2025. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. /episode/index/show/jcopodcast/id/36771155

JCO at ASCO Annual Meeting: Lenvatinib Plus Pembrolizumab and Chemotherapy in Gastric Cancer 05/31/2025

JCO at ASCO Annual Meeting: Lenvatinib Plus Pembrolizumab and Chemotherapy in Gastric Cancer JCO Editorial Fellow Dr. Peter Li and JCO Associate Editor Dr. Andrew Ko discuss the ASCO 25 Simultaneous Publication paper "." Transcript The guest on this podcast episode has no disclosures to declare. Dr. Peter Li: Hello, everyone, and welcome to our 2025 ASCO Annual Meeting Series where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's meeting. I'm your host, Dr. Peter Li, JCO Editorial Fellow, and I'm joined by Dr. Andrew Ko, JCO Associate Editor, to discuss the Journal of Clinical Oncology article and abstract presentation "." Now, let's start off with the relevance of this article. Andrew, can you please explain this to our listeners? Dr. Andrew Ko: Sure. Thanks, Peter. So, this was a very large international study evaluating the combination of lenvatinib and pembrolizumab. And just for context, that combination has been approved for use in other solid tumor types. It's FDA approved for renal cell carcinoma, for example, and endometrial carcinoma. But this study was looking specifically at this combination together with a chemotherapy backbone - so either FOLFOX or CAPOX - and comparing that to what at the time was a standard of care, which was just standard chemotherapy by itself. So, this very large study was intending to look at this particular novel combination. And we can get into some of the nuances of this study because the way that the experimental, the combination arm, was designed was perhaps a little bit more on the unusual side and led to maybe some imbalance in terms of how we think about the respective arms. Dr. Peter Li: Okay. We can definitely talk more about that as we go on. So, what are some of the key results of this study, and how do you think this will impact practice in the future? Dr. Andrew Ko: That's a good question. Technically, it was not a positive study. Well, it was positive in the sense that the co-primary endpoints - which included both progression-free survival and overall survival - so, progression-free survival, it did technically meet its endpoint, both in terms of the overall population and the preplanned subgroup analysis of patients who had a PD-L1 CPS of greater than or equal to 1. So, there was a PFS benefit with the experimental combination - the lenvatinib, pembrolizumab, plus chemotherapy - compared to chemotherapy alone. I will say the benefit was on the more modest side. So, if you even look at the medians, it was not a marked difference. If you look at the hazard ratios, they did meet statistical significance. On the other hand, this did not translate into a benefit for overall survival. So, when you ask, "Well, is this going to inform practice?" I'd have to say no. It highlights, I think, that JCO does want to publish articles that aren't necessarily going to be practice-changing, but that I think offer a lot of insights into trial design and important aspects of investigating novel treatments, even if they don't end up moving the needle in routine clinical practice. Dr. Peter Li: I totally agree with you. I mean, it was significant in terms of progression-free survival, but again, not clinically significant. And then overall survival, the interventional arm actually appeared to do slightly worse overall. Can you make some comments on the strengths and the weaknesses of this study, and where do you see us going from here? Dr. Andrew Ko: So, I think a couple of things worth highlighting in this study, very well designed, more than 800 patients in total. So, first of all, as I mentioned at the beginning, the combination was a little bit unique in terms of patients enrolled to the experimental arm got the combination of lenvatinib, pembrolizumab, together with chemotherapy for a very finite duration. So, that period of chemotherapy they received was only three months. And per protocol, patients then just segued to, quote unquote “maintenance treatment” with just the lenvatinib and pembrolizumab combination. Whereas patients on the control arm, meaning chemotherapy alone, would continue chemotherapy basically in perpetuity until their disease progressed or intolerable toxicity. So, there really was an imbalance in terms of, if you think that chemotherapy or continuing chemotherapy beyond that initial three-month period of time may be significant, that could have had some impact on the robustness or the efficacy of the experimental arm. There were some other aspects in terms of perhaps some differences in the rates of post-progression treatment, in other words, patients going on to receive second-line treatment. I think the other very relevant aspect, Peter, in this study was that the control arm - and no fault of the investigators - but the control arm at the time the study was ongoing just consisted of chemotherapy, FOLFOX CAPOX, by itself, without an immune checkpoint inhibitor, right? And we clearly know, based on results of several large phase III studies, and it's now in standard clinical practice, that we routinely use chemotherapy plus an immune checkpoint inhibitor. Certainly for patients with CPS PD-1/PD-L1 scores that are, well, you could argue greater than 1, or perhaps greater than 5 or 10. But the point being that the control arm of the study probably doesn't reflect what is currently used in clinical practice. And that's just always a challenge in clinical trial design, right? That when a study is designed and when it rolls out, you're always at risk in a rapidly changing and moving field that the standard of care may evolve during the lifetime of that particular trial, which is what I think you see in LEAP-015. Dr. Peter Li: Totally understand. And the survival we see from this study is also roughly similar to the combination of immuno-chemotherapy that is the standard of care today, which is, the authors mentioned, 12 to 14 months. Thank you so much, Andrew, for your input and for speaking about the JCO article "Lenvatinib Plus Pembrolizumab and Chemotherapy Versus Chemotherapy in Advanced Metastatic Gastroesophageal Adenocarcinoma: The Phase III Randomized LEAP-015 Study." Join us again for the latest simultaneous publications from the 2025 ASCO Annual Meeting. Please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of ASCO 2025. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. /episode/index/show/jcopodcast/id/36795520

JCO Article Insights: Double Hit Myeloma Correlates With Adverse Patient Outcome 05/29/2025

JCO Article Insights: Double Hit Myeloma Correlates With Adverse Patient Outcome In this JCO Article Insights episode, host Michael Hughes summarizes "Co-Occurrence of Cytogenetic Abnormalities and High-Risk Disease in Newly Diagnosed and Relapsed/Refractory Multiple Myeloma" by Kaiser et al, published February 18, 2025, followed by an interview with JCO Associate Editor Suzanne Lentzsch. Transcript Michael Hughes: Welcome to this episode of . This is Michael Hughes, JCO's editorial fellow. Today I have the privilege and pleasure of interviewing Dr. Suzanne Lentzsch on the “” by Dr. Kaiser and colleagues. At the time of this recording, that will be linked in the transcript. The urge to identify patients with aggressive disease, which is the first step in any effort to provide personalized medical care, is intuitive to physicians today. Multiple myeloma patients have experienced heterogeneous outcomes since we first started characterizing the disease. Some patients live for decades after treatment. Some, irrespective of treatment administered, exhibit rapidly relapsing disease. We term this ‘high-risk myeloma’. The Durie-Salmon Risk Stratification System, introduced in 1975, was the first formal effort to identify those patients with aggressive, high-risk myeloma. However, the introduction of novel approaches in therapeutic agents—autologous stem cell transplantation with melphalan conditioning, proteasome inhibitors like bortezomib, or immunomodulatory drugs like lenalidomide—rendered the Durie-Salmon system a less precise predictor of outcomes. The International Staging System in 2005, predicated upon the burden of disease as measured by beta-2 microglobulin and serum albumin, was the second attempt at identifying high-risk myeloma. It was eventually supplanted by the Revised International Staging System (RISS) in 2015, which incorporated novel clinical and cytogenetic markers and remains the primary way physicians think about the risk of progression or relapse in multiple myeloma. Much attention has been focused on the canonically high-risk cytogenetic abnormalities in myeloma, typically identified by fluorescence in situ hybridization: translocation t(4;14), translocation t(14;16), translocation t(14;20), and deletion of 17p. Much attention also has been focused on the fact that intermediate-risk disease, as defined by the RISS, has been shown to be a heterogeneous subgroup in terms of survival outcomes. The RISS underwent revision in 2022 to account for such heterogeneity and has become the R2-ISS, published here in the Journal of Clinical Oncology first in 2022. Translocations t(14;16) and t(14;20) were removed, and gain or amplification of 1q was added. Such revisions to core parts of a modern risk-stratification system reflect the fact that myeloma right now is in flux, both in treatment paradigms and risk-stratification systems. The field in recent years has undergone numerous remarkable changes, from the advent of anti-CD38 agents to the introduction of cellular and bispecific therapies, to the very technology we use to investigate genetic lesions. The major issue is that we're seeing numerous trials using different criteria for the definition of high-risk multiple myeloma. This is a burgeoning problem and speaks very much now to a critical need for an effort to consolidate all these criteria on at least cytogenetic lesions as we move into an era of response-adapted treatment strategies. The excellent article by Kaiser and colleagues, published in the February 2024 edition of the JCO, does just that in a far-ranging meta-analysis of data from 24 prospective therapeutic trials. All 24 trials were phase II or III randomized controlled trials for newly diagnosed and relapsed/refractory multiple myeloma. The paper takes a federated analysis approach: participants provided summaries and performed prespecified uniform analyses. The high-risk cytogenetic abnormalities examined were translocation t(4;14), gain or amplification of 1q, deletion of 17p, and translocation t(14;16), if included in the original trials. All of these were collected into zero, single, or double-hit categories, not unlike the system currently present in diffuse large B-cell lymphomas. The outcomes studied were progression-free survival and overall survival, with these analyses adhering to modified ITT principles. The authors also performed prespecified subgroup analyses in the following: transplant-eligible newly diagnosed myeloma, transplant non-ineligible newly diagnosed myeloma, and relapsed/refractory myeloma. They, in addition, described heterogeneity by the I2 statistic, which, if above 50%, denotes substantial heterogeneity by the Cochrane Review Handbook, and otherwise performed sensitivity analyses and assessed bias to confirm the robustness of their results. In terms of those results, looking at the data collected, there was an appropriate spread of anti-CD38-containing and non-containing trials. 7,724 patients were evaluable of a total 13,926 enrolled in those 24 trials: 4,106 from nine trials in transplant-eligible myeloma, 1,816 from seven trials in transplant non-ineligible myeloma, and 1,802 from eight trials in relapsed/refractory disease. ISS stage for all patients was relatively evenly spread: stage I, 34.5%; stage II, 37%; stage III, 24%. In terms of high-risk cytogenetic lesions, double-hit disease was present in 13.8% of patients, and single-hit disease was present in 37.4%. In terms of outcomes, Kaiser and colleagues found a consistent separation in survival outcomes when the cohort was stratified by the number of high-risk cytogenetic lesions present. For PFS, the hazard ratio was for double-hit 2.28, for single-hit 1.51, without significant heterogeneity. For overall survival, the hazard ratio was for double-hit disease 2.94, single-hit disease 1.69, without significant heterogeneity except in patients with double-hit disease at 56.5%. By clinical subgroups, hazard ratios remained pretty consistent with the overall cohort analysis. In transplant-eligible newly diagnosed myeloma, the hazard ratio for progression is 2.53, overall survival 4.17. For transplant non-ineligible, 1.97 progression, 2.31 mortality. Relapsed/refractory disease progression 2.05, overall mortality 2.21, without significant heterogeneity. Of trials which started recruitment since 2015, that is to say, since daratumumab was FDA approved and thus since an anti-CD38 agent was incorporated into these regimens, analysis revealed the same results, with double-hit myeloma still experiencing worse survival by far of the three categories analyzed. Risk of bias overall was low by advanced statistical analysis. In terms of subgroup analysis, double-hit results for transplant-eligible newly diagnosed myeloma may have been skewed by smaller study effects, where the upper bound of the estimated hazard ratio for mortality reached into the 15 to 20 range. In conclusion, from a massive amount of data comes a very elegant way to think about the role certain cytogenetic abnormalities play in multiple myeloma. A simple number of lesions - zero, one, or at least two - can risk-stratify. This is a powerful new prognostic biomarker candidate and, somewhat soberingly, also may confirm, or at least suggests, that anti-CD38 agents are unable to overcome the deleterious impact of certain biologic characteristics of myeloma. Where do we go from here? This certainly needs further a priori prospective validation. This did not include cellular therapies. The very scale at which this risk-stratification system operates, agnostic to specific genetic lesion, let alone point mutations, lends itself also to further exploration. And to discuss this piece further, we welcome the one and only to the episode. Dr. Lentzsch serves as an associate editor for JCO and is a world-renowned leader at the bleeding edge of plasma cell dyscrasia research. Dr. Lentzsch, there are several new investigations which suggest that translocation t(4;14), for example, is itself a heterogeneous collection of patients. There are other studies which suggest that point mutations in oncogenes like TP53, which were not assessed in Kaiser et al., carry substantial detrimental impact. Is this classification system - no-hit, single-hit, double-hit - too broad a look at tumor genetics? And how do you think we will end up incorporating ever more detailed investigations into the genetics of multiple myeloma moving forward? Dr. Suzanne Lentzsch: Michael, first of all, excellent presentation of that very important trial. Great summary. And of course, it's a pleasure to be here with JCO and with you to discuss that manuscript. Let me go back a little bit to high-risk multiple myeloma. I think over the last years, we had a lot of information on what is high-risk multiple myeloma, and I just want to mention a couple of things, that we separate not only cytogenetically high-risk multiple myeloma, we also have functional high-risk multiple myeloma, with an early relapse after transplant, within 12 months, or two years after start of treatment for the non transplant patients, which is difficult to assess because you cannot decide whether this is a high-risk patient before you start treatment. You only know that in retrospective. Other forms of high-risk: extramedullary disease, circulating tumor cells/plasma cell dyscrasia, patients who never achieve MRD positivity, extramedullary multiple myeloma, or even age and frailty is a high risk for our patients. Then we have gene expression and gene sequencing. So there is so much information currently to really assess what is high-risk multiple myeloma, that is very difficult to find common ground and establish something for future clinical trials. So what Dr. Kaiser did was really to develop a very elegant system with information we should all have. He used four factors: translocation t(14;16), t(4;14), gain or amplification of 1q, and deletion of 17p. Of course, this is not the entire, I would say, information we have on high risk, but I think it's a good standard. It's a very elegant system to really classify a standard single-hit, double-hit, high-risk multiple myeloma, which can be used for all physicians who treat multiple myeloma, and especially, it might also work in resource-scarce settings. So, ultimately, I think that system is an easy-to-use baseline for our patients and provides the best information we can get, especially with a baseline, in order to compare clinical trials or to compare any data in the future. Michael Hughes: Thank you, Dr. Lentzsch. To the point that you made about this isn't the full story. There does, as you said, exist this persistent group of functional high-risk multiple myeloma where we see standard-risk cytogenetics, but these patients ultimately either exhibit primary refractory disease or very early relapse despite aggressive, standard aggressive treatment. How do you see risk-stratification systems incorporating other novel biomarkers for such patients? Is it truly all genetic? Or is next-generation sequencing, gene expression profiling, is that the answer? Or is there still a role for characterizing tumor burden? Dr. Suzanne Lentzsch: Excellent question, Michael, and I wish I would have the glass ball to answer that question. I see some problems with the current approach we have. First of all, to do the cytogenetics, you need good material. You only detect and identify what you have. If the bone marrow is of low quality, you have mainly peripheral blood in your bone marrow biopsy, you might not really fully have a representation of all cytogenetic changes in your bone marrow. So I think with a low-quality sample, that you might miss one or the other really cytogenetic high risk. So, having said this, I think circulating tumor cells, that might be something we will look into in the future, because circulating tumor cells are readily available, can be assessed without doing a bone marrow biopsy. And what is even more exciting, in addition to the circulating tumor cells or plasma cells, using them is next-generation sequencing. I think at the moment, we are more in a collection phase where we really try to correlate sequencing with our cytogenetics and especially to establish next-generation sequencing in all of our patients. But I think after that collection phase, maybe in the future, collecting peripheral blood and doing sequencing on peripheral blood samples might be the way to go. In addition, I don't want to forget the imaging. We started with a skeletal survey, and we know that you probably need to lose 30% of the bone before you see a lesion at all. So having imaging, such as diffusion-weighted imaging, whole-body MRI, is also, together with sequencing of the tumor cells, a step into the right direction. Michael Hughes: Thank you, Dr. Lentzsch. Bringing this back to the article at hand, how has Kaiser et al. changed the way we discuss myeloma with patients in the exam room? Dr. Suzanne Lentzsch: I think we have more data on hand. So far, we talked about standard risk and high risk, but I think right now, with a very simple system, we can go into the room and we can tell the patient, "Listen, you don't have any of those cytogenetic abnormalities. I think you have a standard risk. We might give you a simple maintenance treatment with Revlimid." But we might also go into the room and say, "I'm really concerned. You have so-called double-hit multiple myeloma. You have high-risk and at least two of those abnormal cytogenetics which we discussed, and I think you need a more intense maintenance treatment, for instance, double maintenance." I think we know that a high-risk multiple myeloma can be brought into a remission, but the problem that we have is to keep those patients into a remission. So, I think a more intense treatment, for instance, with a double maintenance, or with consolidation after transplant, and a longer and more intense treatment is justified in patients who have that truly high-risk multiple myeloma described here. Michael Hughes: Dr. Lentzsch, thank you so much for your time and your wisdom. Dr. Suzanne Lentzsch: My pleasure. Thank you for having me. Michael Hughes: Listeners, thank you for listening to JCO Article Insights. 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