ESMO 2023 |Dr. Girard analyses PAPILLON: Opening new doors for first-line treatment of EGFR Exon 20 insertion-mutated advanced NSCLC

 

Editor's note: Based on the results of the PAPILLON trial, released at the ESMO 2023 Congress Presidential Symposium 1. The bispecific EGFR/MET monoclonal antibody is expected to become the standard of care for advanced or metastatic non-small cell lung cancer (NSCLC) with an EGFR exon 20 insertion mutation, but toxicity has to be managed carefully (Abstract No. LBA5). Study author Nicolas Girard, of the Curie-Montsouris Chest Center, was interviewed by Oncology Frontier at the conference to analyze the clinical implications of this study's findings.

    

Oncology Frontier: 2023 ESMO released the data of Amivantamab plus chemotherapy vs chemotherapy as first-line treatment in EGFR Exon 20 insertion-mutated advanced NSCLC (LBA5). Please share your views on the primary results from Phase 3 global study PAPILLON.

Dr Girard: The PAPILLON trial is the first phase III study to demonstrate a clinical benefit for patients with EGFR Exon 20 insertion-mutated non-small cell lung cancer. This is a small subset of patients. This is very different from the common EGFR mutations for which we have TKIs and many options in the first- and second-line setting. Here, we are dealing with a disease with limited efficacy of standard-of-care, which has remained for a long time of chemotherapy alone. The PAPILLON study enrolled 308 patients with 1:1 randomization to receive amivantamab with chemotherapy versus chemotherapy alone. Those patients randomized to chemotherapy had the opportunity to crossover to receive amivantamab monotherapy upon disease progression. So there was a crossover in this trial. The primary endpoint was progression-free survival by blinded independent central committee review. We showed a benefit in favor of amivantamab with chemotherapy in terms of PFS, so the PAPILLON study met its primary endpoint. This was 11.4 months versus 6.7 months with a hazard ratio of 0.395 - so a very important reduction in the risk of disease progression, and this is highly significant. We also have data regarding response rate, which is significantly higher with amivantamab with chemotherapy versus chemotherapy alone. We have a longer duration of response. We have a longer PFS2, which is the duration between randomization and second disease progression, which was not reached in the amivantamab with chemotherapy group. This was 17 months with chemotherapy alone. Again, these results are despite the fact that we have a crossover in two-thirds of the patients from the control arm, where they had the opportunity to receive amivantamab monotherapy in the second-line setting. With regard to safety, the profile is manageable. It is expected, given the mechanism of action of amivantamab, that we have side effects related to EGFR inhibition and MET inhibition. But in the end, the rate of treatment discontinuation in this setting was low at 7%. In the end, the PAPILLON study shows a clinical benefit with this combination in the first-line setting of amivantamab with chemotherapy. This is a new standard-of-care for these patients 

Oncology Frontier: what's current and future directions for EGFR exon 20 insertion mutations in NSCLC?

Dr Girard: That is a very good question. There is a matter of identification of these patients. This requires next-generation sequencing (NGS). It is easy to miss one of these EGFR Exon 20 insertions, because there are many of these. It is a complex identification process that requires NGS and not just testing for a single insertion. This is the first challenge. Obviously, we need to understand the mechanism of resistance to define our sequencing of treatment. There are other therapies that are under development for the treatment of these patients, especially using TKIs. So we have to understand how to sequence these different options. Re-biopsy to identify the mechanism of resistance is something of interest in this patient population. We are starting to understand who are the patients most likely to benefit, and those who will be refractory to this combination. Again, this may be related to the type of EGFR insertion. There are many of these, and we probably need to go deeper into the analysis of the PAPILLON study for this matter. There are also some challenges in the selection of patients. These patients may have aggressive disease. Some of the patients have CNS involvement. So we need to go deeper again into the analysis of this patient subset. This is the first report from PAPILLON, an interim analysis, so this will continue particularly regarding overall survival, which was not mature at the time of this presentation. There is still a lot to report from this clinical trial. 

Oncology Frontier: Please talk about the strategies for overcoming EGFR resistance in NSCLC patient management.

Dr Girard: That’s a very good question. In the common EGFR mutation setting after osimertinib, we know that the most frequent alterations are those of the MET gene with MET amplification, observed in 15-20% of patients. This is the rationale to combine EGFR inhibition with MET inhibition. This is what amivantamab is doing as a bispecific antibody targeting EGFR and MET. We will have data during this meeting for the combination of amivantamab with lazertinib, a third-generation TKI for patients with common EGFR mutations, in the first-line setting, and in the second-line setting after failure of osimertinib, amivantamab with lazertinib and chemotherapy. How to interpret these combinations in the field of EGFR Exon 20 is very difficult to know. The efficacy of amivantamab is probably related to a deeper inhibition of the EGFR signaling pathway, and probably related to cMET inhibition as well, so protecting the patient against the emergence of a MET-driven resistance and disease progression. Amivantamab also has immune cell-directing activity. We see with amivantamab a kind of long term progression-free survival benefit, similar to what we have with the immune checkpoint inhibitors - we have this sustained efficacy. We had that in CHRYSALIS with amivantamab monotherapy. We had that in PAPILLON as well. So it is a hint that we also have this immune-driven mechanism of action, and this probably contributing to outcomes. 

Oncology Frontier: The 2023 ESMO has released the results of a number of thoracic cancer studies,which studies are you most interested in?

Dr Girard: Obviously, in the metastatic field, we have the first data from a phase III study with an ADC (antibody-drug conjugate), datopotamab deruxtecan in the TROPION-Lung01 trial, that is presented on Monday. We have to see the data. This is the first time we have had a randomized study with such a mechanism of action in a few different cancers. So very interesting data. We have also many data regarding the perioperative strategies, and how to select neoadjuvant only, adjuvant only, or both (neoadjuvant plus adjuvant). We need to understand who are the patients benefiting from adjuvant versus neoadjuvant. So there is a lot here in the perioperative setting as well, and this is important because, in the future, we will have fewer patients with metastatic disease with thoracic cancer, and more patients with early stage disease because of intensive screening. So it is important to also have improvements in the field of resectable tumors.

Oncology Frontier: Our audience is from China, where the EGFR Exon 20 insertion population is quite small. But we are seeing more and more lung cancer patients in China. Do you have anything you would like to share with your Chinese colleagues?

Dr Girard: I believe it is a small subset, but then it is many people. We are reducing by 60% the risk of disease progression. We need a longer follow-up than what we have to understand the full impact on overall survival, but at this time, we have a trend towards benefit in terms of overall survival. So, this is the way things are moving - identifying this subset of patients, making progress in that subset, and the end result is improved survival in these types of patients in a population that is increasing. We see that worldwide. We have seen that with immune checkpoint inhibitors as well with a doubling in the survival of patients with lung cancer overall. This is the main objective. The key point is to have these personalized strategies for all patients with lung cancer, and for each patient, to find the best individualized strategy to improve the outcome for each single patient.