JCO Article Insights: Pooled Taletrectinib Efficacy and Safety

In this JCO Article Insights episode, host Peter Li summarizes "Taletrectinib in ROS1-Mutated Non–Small Cell Lung Cancer: TRUST" 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 JCO Article Insights. I am Dr. Peter Li, JCO’s editorial fellow, and today I am joined by Dr. Maurice Pérol on “Taletrectinib in ROS1-Mutated Non–Small Cell Lung Cancer: TRUST,” 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.

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