Big Survival Gain in EGFR-Mutant NSCLC

PARIS — Final overall survival results from the phase 3 MARIPOSA study showed that the first-line amivantamab plus lazertinib combination extended overall survival notably more than osimertinib in advanced epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancer (NSCLC).

More specifically, the combination led to a statistically significant and clinically meaningful reduction in mortality compared with osimertinib (hazard ratio [HR], 0.75; P < .005), presenter James Chih-Hsin Yang, MD, PhD, professor and director, Graduate Institute of Oncology, National Taiwan University, Taipei, Taiwan, told the audience at the European Lung Cancer Congress 2025. Median overall survival in the combination group was not reached by the 37.8-month median follow-up compared with 36.7 months in the osimertinib group.

“You’ll want to take a closer look — maybe take a photograph,” said Yang when he called up the slide with the overall survival findings.

Lazertinib is an oral, highly selective, third-generation EGFR tyrosine kinase inhibitor that can penetrate the brain, and amivantamab is a bispecific antibody targeting EGFR and mesenchymal-epithelial transition (MET).

The MARIPOSA trial randomly assigned 1074 patients with EGFR exon 19 deletion or exon 21 L858R substitution mutation–positive locally advanced or metastatic NSCLC and no prior systemic therapy to amivantamab plus lazertinib, osimertinib alone, or lazertinib alone.

Earlier results from the MARIPOSA study showed that the combination reduced the risk for disease progression or death by 30% compared with osimertinib and led to United States Food and Drug Administration approval of the combination last year as an upfront treatment of advanced EGFR-mutant NSCLC.

The latest results compared the overall survival outcomes in the amivantamab plus lazertinib combination arm and the osimertinib arm.

Overall, patients receiving the combination lived significantly longer than those treated with osimertinib. At 3 years, 60% of participants in the amivantamab plus lazertinib group were alive vs 51% in the osimertinib group. The benefit continued to widen at 42 months, with survival rates of 56% vs 44%, respectively. And a “generally consistent” overall survival benefit for the combination over osimertinib was observed across all predefined subgroups, Yang reported.

Treatment with amivantamab plus lazertinib also led to clinically meaningful improvement in intracranial progression-free survival (PFS). The 3-year intracranial PFS was 36% with the combination vs 18% with osimertinib (HR, 0.79). Median intracranial PFS was 25.4 months with the combination vs 22.2 months with osimertinib. Intracranial duration of response also improved with the combination (median, 35.7 months vs 29.6 months).

In addition, time to symptomatic progression was delayed by more than 14 months with amivantamab plus lazertinib vs osimertinib (median, 43.6 months vs 29.3 months; HR, 0.69).

Putting the MARIPOSA findings into perspective, Yang explained that 15 years ago, overall survival with the first-generation EGFR tyrosine kinase inhibitor gefitinib was 20 months. With the third-generation EGFR inhibitor osimertinib, overall survival time increased to just over 3 years. Now, by combining amivantamab and lazertinib, “we can potentially extend median survival beyond 4 years,” he said.

The Potential Adverse Event (AE) Problem

Looking at the safety profile of the combination, AEs occurred much more frequently in the combination arm.

AEs with the combination were mostly grades 1-2 and related to EGFR inhibition (rash, nail toxicity, diarrhea, dermatitis acneiform, stomatitis, and pruritus) and MET inhibition (hypoalbuminemia and peripheral edema). Venous thromboembolism occurred in 40% of the amivantamab plus lazertinib group vs 11% of the osimertinib group.

Yang noted that most AEs occurred in the first 4 months of treatment with the combination. No new safety signals emerged with longer-term follow-up, indicating that long-term treatment is feasible. He also explained that “simple and accessible” prophylactic interventions could substantially reduce the incidence of these AEs, and a growing body of evidence showed such interventions are effective.

Invited discussant Maurice Pérol, MD, medical oncologist and head of Thoracic Oncology at the Léon Bérard Cancer Center, Lyon, France, noted that, although the combination achieved a significant and clinically relevant overall survival benefit over osimertinib, this benefit comes “at the cost of a significant early and [potentially] long-lasting toxicity, requiring aggressive management and impacting the daily quality of life.”

Given the rates of toxicities, “this is clearly a situation for a shared decision-making process and discussing with the patient his or her priorities with regard to the treatment objective,” said Pérol. 

The MARIPOSA trial was funded by Janssen Research & Development, LLC. Yang and Pérol disclosed various relationships with Janssen and other pharmaceutical companies.