April 23, 2026 | Caroline Seymour
Second-line progression-free survival (PFS) was significantly improved in patients with treatment-naive, locally advanced or metastatic EGFR-mutant non–small cell lung cancer (NSCLC) who had received amivantamab-vmjw (Rybrevant) plus lazertinib (Lazcluze) vs osimertinib (Tagrisso) in the first-line setting, as well as in those with unknown vs known resistance mechanisms irrespective of treatment, according to findings from a post hoc analysis of the phase 3 MARIPOSA trial (NCT04487080).1
Data shared during the 2026 AACR Annual Meeting showed that, at a median follow-up of 37.9 months (range, 1.8-48.1), the median second-line PFS in patients who initiated a first subsequent therapy favored the combination arm, at 8.4 months (95% CI, 6.4-10.9) vs 5.3 months (95% CI, 4.6-6.5) in the monotherapy arm (HR, 0.72; 95% CI, 0.54-0.95; P = .02).
“With clinically meaningful increases in first-line PFS and second-line PFS, initiating treatment with amivantamab and lazertinib provides long-term durable efficacy,” David R. Spigel, MD, lead study author and chief scientific officer of Sarah Cannon Research Institute in Nashville, Tennessee, and coauthors wrote in the poster.
Notably, subsequent treatments were comparable after frontline therapy, lessening the effect on second-line PFS. The most common subsequent treatments in the combination and monotherapy arms, respectively, included platinum (52% vs 66%) and/or EGFR-directed therapy (47% vs 32%). The percentage of patients who received radiation after frontline therapy (11% vs 12%) or concurrent administration with second-line therapy (1% each) was similar across the combination and monotherapy arms, respectively.
“The ability of the amivantamab and lazertinib regimen to change the underlying biology of disease is an important factor in EGFR-mutated NSCLC and may contribute to the substantially improved first-line PFS, second-line PFS, and OS [overall survival] observed in MARIPOSA,” the authors concluded.
What served as the basis to evaluate second-line PFS?
MARIPOSA, which prohibited crossover, previously reported an improvement in both PFS and OS with the use of amivantamab and lazertinib (n = 429) vs osimertinib (n = 429) as frontline therapy in patients with locally advanced or metastatic EGFR-mutant (exon 19 deletion or L858R) NSCLC.2 Additionally, use of the combination was associated with fewer acquired MET amplifications (3.4% vs 13.1%; P = .002) and EGFR resistance mutations (C797S, L718X, G724X: 1.4% vs 7.6%; P = .01) vs with osimertinib.1
“EGFR/MET-independent resistance mechanisms were similar between treatment arms, although unknown resistance was higher in the amivantamab and lazertinib vs osimertinib arm, at 68% vs 59%, respectively,” the authors said.
The implications of known vs unknown resistance on overall prognosis are not well understood. However, authors postulated that the assessment of another key efficacy end point, time to second progression or death, could be biased due to the substantial PFS improvement reported with the combination vs monotherapy in the trial.
As such, investigators evaluated second-line PFS in patients enrolled in the study, measured from the time of first subsequent therapy start, including associations between resistance mechanisms and second-line outcomes.
MARIPOSA Post Hoc Analysis: Key Takeaways
- The combination of amivantamab and lazertinib improved second-line PFS vs osimertinib (8.4 vs 5.3 months; HR, 0.72).
- Longer PFS was reported in patients with unknown vs known resistance (7.4 vs 4.6 months; HR, 0.63).
- Findings support durable efficacy and potential disease biology modification with first-line combination therapy.
What parameters were used to measure efficacy?
Second-line PFS was defined as the time from the start of the first subsequent therapy to investigator-assessed second progressive disease, or death. End-of-treatment resistance was determined by evaluating circulating tumor DNA in liquid biopsy samples run through the Guardant360 next-generation sequencing panel.
Known resistance mechanisms included detectable EGFR/MET-dependent (C797S, MET amplification) and/or EGFR/MET-independent resistance (HER2 amplification, PIK3CA, RAS/RAF, cell cycle, TP53/Rb1 loss of function) acquired through activation of alternative bypass pathways, abnormal downstream signaling, or histologic transformation.
The absence of these identifiable alterations would serve to be represented as unknown resistance.
What were the baseline demographic and clinical characteristics of patients who received a first subsequent therapy?
The clinical cutoff for the final analysis was December 4, 2024, at which point 154 patients in the combination arm and 209 in the monotherapy arm had received a first subsequent therapy. End of treatment data pertaining to resistance were available for 92 and 134 patients, respectively.
“Baseline demographic and clinical characteristics were well balanced between treatment arms,” the authors wrote.
In the combination arm (n = 154) the median age was 63 years (range, 25-81) and most patients were female (n = 88; 57%). Patients were either Asian (n = 86; 56%), White (n = 62; 40%), or other (n = 6; 4%) and most had an ECOG performance status of 1 (n = 106; 69%). The minority of patients had a smoking history (n = 60; 39%) and brain metastases (n = 64; 42%), and EGFR exon 19 deletion (n = 85; 55%) was slightly more common than an L858R mutation (n = 70; 45%).
In the monotherapy arm (n = 209) the median age was 60 years (range, 28-87) and most patients were female (n = 112; 54%). Patients were predominantly Asian (n = 125; 60%) vs White (n = 79; 38%) or other (n = 5; 2%). ECOG performance status was 1 in 67% (n = 140) of cases. Most patients had no smoking history (n = 141; 67%) nor brain metastases (n = 117; 56%), and EGFR mutation type was more often an exon 19 deletion (n = 133; 64%) than an L858R mutation (n = 76; 36%).
What additional findings were shared during the meeting?
In both arms combined, the median second-line PFS also favored patients with unknown resistance mechanisms, at 7.4 months (95% CI, 5.3-9.9) vs 4.6 months (95% CI, 3.8-5.3) in those with known resistance mechanisms (HR, 0.63; 95% CI, 0.45-0.90; P = .01).
“The median second-line PFS was consistent for EGFR/MET-dependent and EGFR/MET-independent subgroups within the known resistance subset, and tumor size was balanced across resistance mechanisms at baseline and end of treatment,” the authors concluded.
Disclosures: Spigel served in a leadership role for ASCO; served in a consulting or advisory role for Genentech/Roche, Novartis, Bristol Myers Squibb, AstraZeneca, Pfizer, GSK, Takeda, Evelo Therapeutics, Bayer, EMD Serono, Molecular Templates, Amgen, Curio Science, Intellisphere, Ipsen, Jazz Pharmaceuticals, Mirati Therapeutics, Puma Biotechnology, Sanofi/Aventis, Exelixis, Novocure, Regeneron, Eli Lilly, Johnson & Johnson, and Evidera; received research funding from Genentech/Roche, Novartis, Celgene, Bristol Myers Squibb, Eli Lilly, AstraZeneca, University of Texas Southwestern Medical Center – Simmons Cancer Center, Merck, G1 Therapeutics, Neon Therapeutics, Takeda, Nektar, Celldex, Clovis Oncology, Daiichi Sankyo, EMD Serono, Astellas Pharma, GRAIL, Transgene, Aeglea BioTherapeutics, Ipsen, BIND Therapeutics, Eisai, ImClone Systems, ImmunoGen, Johnson & Johnson Oncology, MedImmune, Molecular Partners, Agios, GSK, Tesaro, Cyteir, Apollomics, Novocure, Elevation Oncology, Calithera Biosciences, Arcus Biosciences, Arrys Therapeutics, Bayer, BeiGene, BioNTech, Blueprint Medicines, Boehringer Ingelheim, Denovo Biopharma, Hutchison MediPharma, Incyte, Kronos Bio, Loxo Oncology, MacroGenics, Molecular Templates, Oncologie, Pfizer, PTC Therapeutics, PureTech, Razor Genomics, Repare Therapeutics, Rgenix, Tizona Therapeutics, and Verastem; and received travel, accommodations, and expenses from AstraZeneca, Genentech, and Novartis.
References
Spigel DR, Nguyen D, Hayashi H, et al. Impact of first-line amivantamab plus lazertinib versus osimertinib on second-line progression-free survival. Presented at: 2026 American Association for Cancer Research Annual Meeting; April 17-22, 2026; San Diego, CA. Abstract LB474/21.
Chih-Hsin Yang J, Lu S, Hayashi H, et al. Overall survival with amivantamab-lazertinib in EGFR-mutated advanced NSCLC. N Engl J Med. 2025;393(17):1681-1693. doi:10.1056/NEJMoa2503001.
