Key Clinical Summary: 

• Design/Population: This post hoc analysis of the phase 3 MARIPOSA trial evaluated second-line progression-free survival in patients with EGFR-mutated advanced NSCLC treated with first-line amivantamab plus lazertinib or osimertinib.
• Key Outcomes: Patients receiving amivantamab plus lazertinib had improved second-line progression-free survival compared with those receiving osimertinib. Known resistance mechanisms were associated with worse outcomes than unknown resistance patterns.
• Clinical Relevance: These findings suggest that first-line treatment choice may influence long-term outcomes by altering resistance biology. Amivantamab plus lazertinib may provide more durable disease control across treatment lines.

According to post hoc analysis results from the phase 3 MARIPOSA trial, first-line amivantamab plus lazertinib improves second-line progression-free survival (PFS) compared with osimertinib among patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC).

These findings were presented by David Spigel, MD, Sarah Canon Research Institute, Nashville, Tennessee, at the 2026 American Association for Cancer Research (AACR) Annual Meeting in San Diego, California.

In this study, data were collected from 363 patients enrolled in the MARIPOSA trial who received first-line amivantamab plus lazertinib (n = 154) or osimertinib (n = 209) and subsequently underwent additional therapy. Acquired resistance was assessed using paired baseline and end-of-treatment samples (n = 226), and ctDNA was analyzed by next-generation sequencing. The primary end point was second-line PFS, defined as the time from initiation of first subsequent therapy to second objective disease progression or death in the intention-to-treat population. A key secondary end point was second-line PFS according to resistance mechanisms.

At analysis, resistance profiling revealed that known resistance mechanisms included EGFR/MET-dependent alterations (C797S and MET amplification) and EGFR/MET-independent alterations (PIK3CA, RAS/RAF, cell cycle, and TP53/Rb1 loss-of-function mutations). Patients without these alterations were classified as having unknown resistance.

At a median follow-up of 37.9 months, median second-line PFS was 8.4 months in the amivantamab plus lazertinib arm and 5.3 months in the osimertinib arm (hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.54 to 0.95; P = .02). Median second-line PFS was 4.6 months in patients with known resistance and 7.4 months in those with unknown resistance (HR, 0.63; 95% CI, 0.45 to 0.90; P = .01). 

“Starting with [first-line amivantamab plus lazertinib] provides long-term durable survival,” concluded Dr Spigel. “[Amivantamab plus lazertinib] is the only combination regimen that reduces the most common resistance mechanisms, [and] changing the biology of disease may be an important factor for long-term survival.” 

Source:

Spigel DR, Nguyen D, Hayashi H, et al. Impact of first-line (1L) amivantamab-lazertinib vs osimertinib on second-line (2L) progression-free survival (PFS). Presented at AACR Annual. April 17 - 22, 2026; San Diego, California. LB474.