Based on the results of the PAPILLON trial, presented at Presidential Symposium 1 at the ESMO Congress 2023 (Madrid, Spain, 20-24 October), a dual-specificity EGFR/MET-directed monoclonal antibody has the potential to become a standard of care for EGFR exon 20 insertion-mutated advanced or metastatic non-small cell lung cancer (NSCLC), although toxicity management must be approached with caution (Abstract LBA5). Dr. Nicolas Girard, the leading author of the study and a researcher at the Institute du Thorax Curie-Montsouris (Paris), discussed the implications of these findings for clinical practice in an interview with Oncology Insight conducted during the conference.
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ESMO has released data from the PAPILLON trial comparing Amivantamab in combination with chemotherapy versus chemotherapy as first-line treatment for EGFR exon 20 insertion-mutated advanced NSCLC (Abstract LBA5). Could you share your thoughts on the key results of the international Phase III PAPILLON study?
Dr. Girard: The PAPILLON trial is the first study to demonstrate clinical benefits for patients with EGFR exon 20 insertion-mutated NSCLC in a Phase III study. EGFR exon 20 insertion mutations account for a small subset of NSCLC, and their treatment landscape is very distinct from the common EGFR mutations. Patients with common EGFR mutations have multiple TKI options in both first and second-line treatments, whereas EGFR exon 20 insertion-mutated NSCLC has been a disease with limited treatment options for a long time, typically treated with chemotherapy alone.
The PAPILLON study enrolled 308 patients in a 1:1 randomization to receive either Amivantamab in combination with chemotherapy or chemotherapy alone, with the permission for patients in the chemotherapy control group to cross over to Amivantamab monotherapy upon disease progression, resulting in crossover events during the trial. The primary endpoint was progression-free survival (PFS) assessed by a blinded independent central review committee (BICR).
The PAPILLON trial demonstrated a significant benefit in PFS from the combination of Amivantamab with chemotherapy, achieving its primary endpoint. The median PFS for the Amivantamab group and the control group was 11.4 months and 6.7 months, with a hazard ratio of 0.395, indicating a significant reduction in the risk of disease progression. The response rate with Amivantamab in combination with chemotherapy was significantly higher than with chemotherapy alone, and the duration of response was longer, and a longer PFS2 (time between randomization and second disease progression). PFS2 was not reached in the Amivantamab combination group and was 17.2 months in the chemotherapy group. Approximately two-thirds of the patients in the chemotherapy control group had the opportunity to cross over to receive Amivantamab monotherapy in the second line. In terms of safety, the safety of Amivantamab combination treatment was manageable, with a low discontinuation rate of only 7%. The PAPILLON study suggests that Amivantamab in combination with chemotherapy provides clinical benefit in the first-line treatment of EGFR exon 20 insertion-mutated advanced NSCLC and could become a new standard of care for patients with this type of mutation.
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Could you talk about the current and future directions for the treatment of EGFR exon 20 insertion-mutated NSCLC?
Dr. Girard: That’s a very good question. The first challenge is that the complexity in identification and detection of the various types of EGFR exon 20 insertion-mutations, and it’s easy to miss one if you’re only testing for a single insertion mutation. Next-generation sequencing (NGS) technology is needed to accurately detect these mutations, as they can vary. We also need to understand the mechanisms of resistance in these patients to determine the treatment sequence. Currently, there are multiple treatment options in development, especially the use of TKIs to treat these patients, and we need to figure out how to sequence these different treatment options. Rebiopsy of resistant patients to determine the mechanisms of resistance is an area of active research.
We are starting to understand which patients are most likely to benefit and which patients do not respond to the Amivantamab combination regimen, which may be related to the specific type of EGFR exon 20 insertion mutation. There is a lot to explore in this regard, and we may need to delve deeper into this issue within the PAPILLON study.
There are also challenges in patient selection, as some of these patients may have aggressive disease, and some may have central nervous system (CNS) involvement. So, it’s necessary to further analyze these patient subgroups.
The 2023 ESMO release is the first interim analysis report of the PAPILLON study, and future reports will continue, particularly with respect to overall survival (OS) data. OS had not matured at the time of the 2023 ESMO release. There is much more to report from this clinical trial.
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Could you discuss strategies for overcoming EGFR resistance in NSCLC patient management?
Dr. Girard: That’s a great question. In patients with common EGFR mutations who progress on osimertinib, we know that the most common alteration is in the MET gene, including MET amplification, with an incidence of 15%-20%. This forms the basis of using a dual-specificity antibody like Amivantamab that targets both EGFR and MET inhibition. The 2023 ESMO Congress will also feature data from the MARIPOSA trial, comparing Amivantamab in combination with Lazertinib versus osimertinib as first-line treatment for EGFR mutant NSCLC patients (Abstract LBA14), and data from the MARIPOSA-2 trial comparing Amivantamab with chemotherapy (± Lazertinib) versus chemotherapy for second-line treatment of EGFR mutant NSLCLC patients who have failed from osimertinib treatment (Abstract LBA15). Lazertinib is a third-generation TKI targeting common EGFR mutations.
It is quite challenging to explain the mechanism of action of the Amivantamab combination regimen in the EGFR exon 20 insertion mutation field. The efficacy of Amivantamabmay may related to a deeper inhibition of the EGFR signaling pathway or related to cMET inhibition, thereby protecting patients from developing MET-driven resistance and disease progression. Amivantamab also has immune cell-directed activity, and we have seen a prolonged PFS benefit, similar to the sustained tail effect seen with immune checkpoint inhibitors. This phenomenon was evident in the CHRYSALIS trial with Amivantamab monotherapy and is also present in the PAPILLON trial, suggesting that Amivantamab’s immune cell-directed activity may contribute to improving treatment outcomes.
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The population of patients with EGFR exon 20 insertion mutations in China is relatively small within NSCLC. What advice do you have for research and treatment of Chinese patients?
Dr. Girard: While the population of patients with EGFR exon 20 insertion mutations in NSCLC in China is relatively small, there are still a significant number of patients. In the PAPILLON trial, the combination of Amivantamab with chemotherapy reduced the risk of disease progression by approximately 60%. Longer follow-up time is needed in the future to understand the full impact of this regimen on overall survival (OS), but there is currently a trend toward OS benefit. Therefore, the future direction is to identify patients with EGFR exon 20 insertion mutations, make progress in this subset of patients’ treatment landscape, and ultimately improve the survival of this growing patient population. One key issue is to find personalized treatment strategies for all lung cancer patients, thereby improving treatment outcomes by tailoring individualized treatment strategies for each patient.
