Amivantamab/Lazertinib Efficacy in EGFR+ NSCLC Sustained in MARIPOSA Follow-Up

Shirish M. Gadgeel, MD

The combination of lazertinib (Lazcluze) and amivantamab-vmjw (Rybrevant) demonstrated significantly improved progression-free survival (PFS), intracranial efficacy, and showed promising overall survival (OS) trends compared to osimertinib (Tagrisso) in treatment-naive patients with EGFR-mutated advanced or metastatic non­–small cell lung cancer (NSCLC).¹

The MARIPOSA trial (NCT04487080) evaluated patients with advanced NSCLC harboring EGFR mutations who were treatment-naive. The trial compared the efficacy of amivantamab, a MET bispecific antibody, given in combination with lazertinib, a third-generation EGFR tyrosine kinase inhibitor, vs osimertinib, the current standard of care in this patient population.

The primary end point of the trial was to assess progression-free survival (PFS), with 1074 patients randomized in a 2:2:1 ratio to receive either the combination, lazertinib alone, or osimertinib alone.

According to Shirish M. Gadgeel, MD, key findings from the trial showed that at a median follow-up of 31.1 months, amivantamab with lazertinib outperformed osimertinib across multiple efficacy end points. The intracranial PFS was significantly improved with the combination at 38% vs 18% with standard of care at 3 years. A promising trend in overall survival (OS) was also demonstrated, with the median OS not yet reached for the combination compared with 37.3 months for osimertinib.

Results from the MARIPOSA trial led to the FDA approval of amivantamab plus lazertinib as a first-line treatment for patients with EGFR mutation-positive advanced NSCLC.² These longer follow-up data reinforced the combination's superiority in terms of PFS, intracranial efficacy, and sustainability of treatment benefits.

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In an interview with Targeted Oncology^TM, Gadgeel, chief of the division of hematology/oncology at Henry Ford Cancer Institute, Henry Ford Health in Detroit, Michigan, discussed the longer follow-up data from the MARIPOSA trial.

Targeted Oncology: Could you provide a brief overview of the MARIPOSA trial and its primary objectives?

Gadgeel: The study was conducted in patients with EGFR mutations—exon 19 deletion or L858R mutation—with advanced non–small cell lung cancer who were treatment-naive for their disease. The standard of care in these patients is a third-generation EGFR TKI, specifically in the United States, osimertinib, which has shown a median progression-free survival of approximately 3 years. However, the estimated 5-year survival has been found to be less than 20%, so there is a need for first-line treatments that can provide better outcomes. As good as the outcomes are with third-generation EGFR TKIs like osimertinib, our hope is that we can do even better.

In the MARIPOSA study, a combination of amivantamab, which is an MET bispecific antibody with immune cell–directing activity, was combined with a third-generation EGFR TKI, lazertinib, and advanced as a first-line treatment for common EGFR mutation–positive advanced non–small cell lung cancer patients vs osimertinib. In this trial, 1074 patients were enrolled and randomized in a 2:2:1 fashion, where patients were randomized to amivantamab plus lazertinib, lazertinib alone, or osimertinib alone to assess the contrast of lazertinib to the combination of amivantamab and lazertinib. The primary end point of this study was progression-free survival.

At last year’s ASCO and subsequently in the New England Journal of Medicine, the primary analysis was published, showing a significant improvement in progression-free survival with a hazard ratio of 0.7. In that analysis, there was also a trend in overall survival favoring amivantamab plus lazertinib. That analysis was with a median follow-up of 22 months. This analysis, with a longer follow-up of 31.1 months, focused on end points of intracranial efficacy, post-progression end points like time to treatment discontinuation, time to subsequent treatment, progression-free survival 2, and overall survival.

What were the main findings from this analysis of the study?

What we found was that in each of these efficacy end points, amivantamab and lazertinib performed better than osimertinib. There was improved intracranial progression-free survival with amivantamab; at about 3 years, the intracranial progression-free survival rate was 38% compared with 18% in patients who received osimertinib. Progression-free survival 2, a measure of sustainability of the efficacy, was also longer in patients who received amivantamab plus lazertinib. The median progression-free survival 2 was not reached with amivantamab plus lazertinib, whereas it was 32.3 months in patients who received osimertinib.

Most importantly, with the longer follow-up, we found a promising trend in overall survival favoring amivantamab plus lazertinib. At 31.1 months, the median survival was not reached with the combination, whereas it was 37.3 months in patients treated with osimertinib. What’s interesting is that with longer follow-up, the overall survival curves are widening. At 2 years, the survival rates were 75% and 70%, whereas at three years, the survival rates were 61% with amivantamab and 53% with osimertinib.

With these longer follow-up data, what were the main takeaways?

This longer follow-up has shown that all efficacy end points appear to be improved with the combination of amivantamab plus lazertinib compared with osimertinib, specifically a trend towards improvement in overall survival and improvement in intracranial progression-free survival. Based on the MARIPOSA study, amivantamab plus lazertinib was recently approved as a first-line treatment for patients with common EGFR mutation–positive advanced non–small cell lung cancer. This long-term follow-up shows that amivantamab plus lazertinib continues to demonstrate improved outcomes compared with patients treated with osimertinib.

How do the long-term findings from MARIPOSA strengthen the case for amivantamab and lazertinib in the first-line treatment for these patients?

I think what this data shows is that we have another option for our patients that appears to provide better outcomes, including a trend in improvement. Of course, MARIPOSA is an ongoing study, and there will be a pre-specified overall survival analysis based on formal statistical testing that will be conducted in the future. That will really answer the question of whether this combination provides improved survival.

But I think what this data shows is that amivantamab plus lazertinib, now with FDA approval, is another option that should be considered in every patient. It should be part of the discussion in the shared decision-making process so that the patient’s oncologist, together with the patient, can come to a decision regarding first-line treatment that appears to be most suitable for that particular patient. Having more options in terms of managing these patients is an advantage, and I think that’s the primary result of this analysis and the recent FDA approval. I would say that it would be wrong, at least as of now, to say all patients should get a combination with amivantamab, but I think it becomes an option to discuss and consider.

What are the potential next steps for the study?

As a lung cancer oncologist, I think 2024 marks 20 years since the identification of EGFR mutations as a driver of genetic alteration in lung cancer. In some ways, it is gratifying that 20 years later, we now have more options for these patients that are resulting in better outcomes. So, it is very gratifying to do this presentation at the 20-year anniversary of the discovery of these mutations.

There are several trials being conducted to build upon the results of the MARIPOSA study. One is that there is definitely skin toxicity observed with this combination, which can be limiting in some ways in terms of treating patients with this combination. So, there is a COCOON trial [NCT06120140] being conducted that randomizes patients to enhanced dermatology management while receiving this combination compared with standard dermatologic management to see if this enhanced proactive use of antibiotics, lotions, and steroids provides better control of the skin toxicities associated with this combination.

In addition, there is a subcutaneous formulation of amivantamab being evaluated. Initial results were presented at ASCO this year, and it appears that the infusion-related reactions observed with intravenous amivantamab are less with subcutaneous amivantamab. Not to mention, subcutaneous administration is far more convenient for patients compared to intravenous infusion. So, those are a couple of ways where we are hoping to build upon the results of the MARIPOSA study.

REFERENCES

1. Popat S, Reckamp KL, Califano R, et al. Amivantamab plus chemotherapy vs chemotherapy in EGFR-mutated, advanced non-small cell lung cancer after disease progression on osimertinib: Second interim overall survival from MARIPOSA-2. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA54.

2. FDA approves amivantamab-vmjw with carboplatin and pemetrexed for non-small cell lung cancer with EGFR exon 19 deletions or L858R mutations. News release. FDA. September 19, 2024. Accessed March 13, 2025. https://tinyurl.com/3rtc35xt