MARIPOSA Study: Long-Term Outcomes and Next Steps for Amivantamab Plus Lazertinib in EGFR-Mutant NSCLC

Pharmacy Times® interviewed Shirish Gadgeel, MD, chief of the Division of Hematology/Oncology at Henry Ford Cancer Institute and presenting author at the 2024 World Conference on Lung Cancer (WCLC) in San Diego. In his presentation, Gadgeel discussed longer follow-up data from the phase 3 MARIPOSA study (NCT04988295) which showed first-line treatment with amivantamab-vmjw (Rybrevant; Johnson & Johnson) combined with lazertinib (Lazcluze; Johnson & Johnson) provided consistent benefit across long-term outcomes compared to osimertinib monotherapy in adult patients with advanced non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions (ex19del) or L858R substitution mutations. According to Gadgeel, the data show a strong overall survival (OS) trend favoring amivantamab-vmjw plus lazertinib at approximately 3 years of follow-up.

Pharmacy Times: What was the rationale and focus of the phase 3 MARIPOSA trial presented at the 2024 World Conference on Lung Cancer?

Shirish Gadgeel, MD: So the standard first-line treatment of [patients with] common EGFR mutation-positive, advanced NSCLC for the last about 5 years has been third-generation EGFR [tyrosine kinase inhibitors (TKIs)], and what we've seen is the median survival with that treatment is approximately 3 years, with an estimated real-world, 5-year survival of less than 20%. In addition, patients who start on third-generation EGFR TKIs, only about 25% to 40% of those patients go on to receive subsequent treatment. So these data support that we need first-line treatments with improved efficacy.

Amivantamab is an EGFR bispecific antibody with immune cell-directing activity, and it has shown activity as a single agent, as well as in combination with lazertinib, a third generation EGFR TKI, in patients who had progressed on first-line, third-generation EGFR TKIs, as well as activity in [patients with] exon 20 EGFR mutation-positive disease, and that's a group in which it has already received FDA approval. So based on all that data, this study was conducted to evaluate whether the combination of amivantamab plus lazertinib provides superior efficacy to the previous standard of a third-generation first-line treatment.

Pharmacy Times: What were the key efficacy findings from the phase 3 MARIPOSA trial?

Gadgeel: So, at [the European Society for Medical Oncology Congress (ESMO) 2023], the primary analysis was presented. What I presented at [WCLC] was the longer follow up, with the median follow up of 31 months. So it was 22 months at the first analysis, and this was about a 9-month longer follow up, and what was seen is that we found that there was improved intracranial efficacy, so intracranial progression-free survival rate at 3 years, where the combination was 38%, it was 18% in patients who received osimertinib (Tagrisso; AstraZeneca Pharmaceuticals LP), there was also greater intracranial duration of response, so the median intracranial duration of response was not reached in patients who received amivantamab plus lazertinib, but it was 24.4 months in patients who received osimertinib. In addition, interestingly, patients who had a response and received amivantamab plus lazertinib, 51% of those patients continued to be in response at 3 years, whereas that proportion was 0% in patients who received osimertinib.

So that was the intracranial efficacy. We also looked at post-progression end points, and the amivantamab plus lazertinib combination demonstrated greater time to treatment discontinuation, greater time to subsequent treatment, as well as improved progression-free survival too.

Finally, we updated the survival results. So, at ESMO last year, when the primary analysis presented the first interim analysis, there was a trend in OS that favored amivantamab plus lazertinib, and the hazard ratio at that time was 0.80. Now with longer follow up, what we find is that the OS curves tend to widen. So, at 2 years the survival rates were 75% and 70% in patients treated with amivantamab and Osimertinib, respectively. Now at 3 years, the 3-year survival rate in patients who received amivantamab plus lazertinib was 61%, whereas it was 53% of patients for those who received osimertinib. So, there's a slight increase in their difference in survival now of 8%, whereas it was 5% at 2 years. So, we think that there does appear to be a very promising trend in OS that is favoring amivantamab plus lazertinib. But this is still early analysis and is not the final analysis. The study is continuing, and a pre-specified final analysis based on a form of statistical testing will be performed in the future.

So, I think the longer follow up has shown that the combination of amivantamab plus lazertinib continues to demonstrate improved long-term outcomes vs osimertinib for the first-line treatment of common EGFR mutation-positive NSCLC, and we speculate that this could be a result of the multi-targeted mechanism of action of amivantamab now combined with the third generation TKI that is providing that improved benefit. Based on the MARIPOSA results, the FDA approved this combination for the first-line treatment of EGFR mutation-positive advanced NSCLC.

Participants at the 2024 World Conference on Lung Cancer take in new insights at the event. Image Credit: © Jon Benjamin Photography

Pharmacy Times: What were the safety findings of the phase 3 MARIPOSA trial presented at the 2024 World Conference on Lung Cancer?

Gadgeel: So, for this update that was presented, we really didn't go into safety analysis, but what has been seen is that with the longer follow up, we are not necessarily seeing any new safety signals. So broadly speaking, we think that the safety data that was presented with the first analysis kind of seems to be holding up.

Pharmacy Times: What are next steps for this research following these results?

Gadgeel: I think there are several studies that are looking at building upon the results of MARIPOSA. An example is that there is increased skin toxicity when you combine these 2 drugs than what you would see with single agent, third-generation EGFR TKI, and that can be a factor and a limitation in delivering this treatment. So, there is an enhanced dermatological management that has been developed, and there is a randomized study that is being conducted to evaluate to what extent this enhanced dermatologic management addresses the dermatological toxicities that are seen with this combination as compared to standard dermatologic management.

We also have now the possibility of subcutaneous amivantamab administration being approved. There's already data presented at [the 2024 American Society of Clinical Oncology Annual Meeting] that evaluated subcutaneous amivantamab vs IV amivantamab, and it appeared that subcutaneous amivantamab had much less infusion-related reactions that are seen with IV amivantamab. And I think just from a patient convenience point of view, subcutaneous amivantamab would be better. So, I think these are a couple of examples of how we think that we are going to see if we can build up upon the results of MARIPOSA, both in terms of tolerability and convenience of administration.