JCO Article Insights: Atezolizumab Plus Bevacizumab, Chemotherapy in EGFR, ALK NSCLC

In this JCO Article Insights episode, Rohit Singh provides summary on two articles published in the April 10th issue of the Journal of Clinical Oncology. The first article, "Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Mutated Non–Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04)" describes a randomized, open-label, multicenter, phase III study evaluating the efficacy of atezolizumab plus bevacizumab, paclitaxel, and carboplatin (ABCP ) in EGFR- or ALK-mutated NSCLC that progressed before TKI therapy. The second is the accompanying Oncology Grand Rounds.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Dr. Rohit Singh: Hello and welcome to JCO Article Insights. I'm your host, Dr. Rohit Singh. Today I will provide a summary of a Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Mutated Non–Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04), by Dr. Park and colleagues from Seoul, Korea. The purpose of this study was to evaluate the efficacy and safety of the ABCP regimen based on IMpower150 in patients with EGFR or ALK mutated non-small cell lung cancer who had progressed on prior targeted treatment.  

I will also discuss an Oncology Grand Round case titled "Management of Treatment Resistance in Patients with Advanced EGFR Lung Cancer: Personalization, Parsimony, and Partnership", by Dr. Vallillo and colleagues from Lahey Hospital Medical Center and Tufts University School of Medicine, Boston, Massachusetts. Oncology Grand Round cases help us to give a clinical context to the clinical trial.  

While TKIs are the established standard of care for non-small cell lung cancer harboring driver mutations, most patients will develop resistance to these treatments. Immune checkpoint inhibitors, with or without chemo, have shown clinical benefits of immune checkpoint monotherapy in patients with EGFR-mutated non-small cell lung cancer. Consequently, platinum-based chemo is the standard of care for patients with EGFR TKI failure. This was a phase III, multicenter, open-label, randomized trial conducted at 16 hospitals across the Republic of Korea. Patients diagnosed with stage four non-small cell lung cancer with sensitizing EGFR mutation or ALK translocation were included in the study. Patients were randomly assigned to the ABCP arm or chemo-only arm in a 2:1 ratio. Eligible patients were stratified on the mutation type (EGFR mutation vs. ALK translocation) and the presence of brain metastasis. No crossover to atezolizumab was permitted. 

The recruitment with T790M mutation was capped at 30%. Patients who responded continued to receive maintenance with atezolizumab until disease progression or unacceptable toxicities occurred. If a patient was identified to have an acquired T790M mutation after the failure of a first or second-generation EGFR TKI, the patient had to be treated with a third-generation EGFR TKI before enrollment. The primary endpoint was investigator-assessed objective response rate according to research criteria. The secondary endpoints included overall survival and progression-free survival at one and two years, and the duration of response, along with a safety analysis. Investigators also did an exploratory biomarker analysis based on PD-L1 expression and its correlation with the response. They also analyzed the distribution of tumor-infiltrating lymphocytes, and a cut-off of 20% inflamed score was used to compare the two arms. Overall, 228 patients were enrolled, 154 in the ABCP arm and 74 in the chemo-only arm. Most patients were female at 56.1% and never smokers at 62.7%. Brain metastasis was present in 42.7% of patients. Most patients had previously received EGFR TKI therapy, however, only 8% and 30% received third-generation TKI as first-line therapy in the ABCP arm and  chemo-only arm, respectively. The majority of the patients were EGFR at  90%. 

The median duration of follow-up for the study population was 26 months. The objective response rate in the ABCP arm was significantly higher at 69.5% compared to 42% in the chemotherapy alone arm. The median PFS was significantly longer in the ABCP arm at 8.48 months versus 5.6 months, and the duration of response was similar at around seven months in both arms. The median overall survival was also similar at around 20 months in both arms, with a hazard ratio of 1.01. In the subgroup of patients with brain metastasis at the time of study enrollment, PFS was significantly longer in the ABCP arm at 8.4 months compared to 4.4 months in the chemotherapy-only arm. In contrast, no difference in PFS was observed in the subgroup without brain metastasis. Regarding EGFR mutation status, there was no difference in PFS or OS between the two arms in the EGFR deletion 19 subgroup. However, a favorable PFS was observed in the EGFR L858R subgroup. For those with acquired EGFR T790M mutation, there was no difference in PFS between groups, whereas a favorable PFS was observed in the subgroup without EGFR T790M mutation. 

In the exploratory biomarker analysis, interestingly, the impact on PFS was correlated with PD-L1 expression. The study found that the higher the PD-L1 expression, the better the PFS. In patients with PD-L1 expression of more than 50%, the hazard ratio was 0.24 for PFS. This is an interesting observation. As in previous studies, we have seen that PD-L1 expression does not have a strong association with response to checkpoint inhibitors in patients with driver mutations. Based on the distribution density of tails in the tumor bed, the inflamed score was calculated using artificial intelligence. For patients with 20% of the imflamed score, the ABCP arm has significantly prolonged PFS at 12.9 months compared to 4.8 months. The median number of ABCP treatment cycles was 4, with 12 for atezolizumab and 8 for bevacizumab as maintenance therapy, pemetrexed maintenance was administered for a median of 10 cycles. The incidence of grade 3 or higher side effects was 35.1% in the ABCP arm compared to 15% in the chemotherapy-only arm. Peripheral neuropathy, alopecia, and myalgias were the most prevalent side effects. Interesting notably, 54% of patients in the ABCP arm required treatment interruption or dose modification, and there were three reported deaths in the ABCP arm, two due to pneumonia and one due to cerebral embolic infarction. Around 10 patients or 13.5% of patients in the chemotherapy-only arm required dose interruption or modification.  

In conclusion, patients with EGFR-mutated or translocated non-small cell lung cancer who had failed prior TKI ABCP regimen showed a statistically significant prolongation of PFS and response rate compared to chemo alone. Patients in the subgroup with EGFR L858R, without acquired T790M mutation, and presence of brain met showed more benefit. There was no difference in overall survival, though we need more mature data. Adverse events were higher in the ABCP arm. Interestingly, in the exploratory analysis, a high PD-L1 and an inflamed score of more than 20% showed PFS benefits. Though we need to take into consideration that this trial was done and all the patients were grouped from a single country considering Asian ethnicity. And most importantly, the majority of patients were treated with first- and second-generation TKIs, whereas third-generation TKIs are the standard of care in the United States. 

Coming to the Oncology Grand Round, in this case, we will discuss the management of treatment resistance in patients with advanced EGFR-mutated lung cancer. A patient with a 20-pack-a-year history of tobacco use presents with weight loss and hip pain, found to have a lung mass, skeletal mets, and brain mets, and was diagnosed with lung adenocarcinoma. The patient goes with palliative radiotherapy for the brain mets. Comprehensive tumor Merkel profiling demonstrated an EGFR mutation exon 19 and alteration P53. The patient was started on third-generation EGFR TKI osimertinib. However, after 17 months, the patient has symptomatic disease progression. Usual approach, if feasible, re-biopsy at the time of progression to evaluate for possible new mutations which can guide treatment options. As mentioned earlier, in the trial, acquired resistance to the TKI is inevitable and heterogeneous. There were various mechanisms which have been proposed regarding resistance, including a second-site EGFR alteration, upregulation of bypass pathway, histological transformation to small cell histology, or suboptimal drug penetration. 

There are various approaches after disease progression on EGFR TKI. Combining EGFR-directed therapies to address resistance is an option. Prime results from the MARIPOSA-2 study showed amivantamab plus chemotherapy with or without lazertinib in EGFR-mutated non-small cell lung cancer after disease progression showed a better objective response rate at 64% compared to 36% in the chemo-alone arm. It also showed improved PFS with a median of 6.3 compared to 4.2 in the chemo-alone arm. Combining immune checkpoint inhibitors, EGFR-mutated non-small cell lung, I say has been disappointing in advance of EGFR-mutated non-small cell lung, and combination therapy studies are needed to improve outcomes. Studies, as I discussed ATTLAS, have shown that combining a VEGF inhibitor with ICIs and chemotherapy can lead to a better objective response rate and PFS. However, further clinical trials are needed to figure out the better subgroup of patients who can benefit from this combination.  

Should the TKI be continued beyond progression in EGFR-mutated advanced non-small cell lung cancer? Continuing the primary EGFR TKI treatment beyond progression may be considered for patients with indolent or asymptomatic progression or localized progression. We can consider radiation, surgery, or ablation. This approach will potentially delay the need to change systemic therapy in patients. However, for patients with multifocal disease progression requiring chain systemic therapy it may be more beneficial to switch to next-line systemic therapy options like platinum doublet with or without immunotherapy and VEGF inhibitors. In the case presented, the decision was made to continue osimertinib along with platinum doublet, deferring the addition of immunotherapy and VEGF inhibitor. This choice was based on factors like the patient's history of brain metastases and intracranial control. There is also a high risk of toxicity, especially pneumonitis, with immune checkpoint inhibitors after using targeted therapy, the patient showed clinical and radiographic improvement while on this treatment regimen. 

The decision to continue or change therapy at cancer progression is based on factors like drug tolerability, patient preferences, and specific subgroups with different outcomes, such as those with brain metastasis or specific EGFR mutation subtypes. Choosing between combination therapy strategies that concept progression involves personalized decision-making to optimize treatment outcomes. Ultimately, the approach to management should be tailored to individual patient needs, preferences, and eligibility for different treatment modalities. 

This is Rohit Singh. Thank you for listening to JCO Article Insights. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You will find all the ASCO shows at asco.org/podcasts. Thank you.

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