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The combination of amivantamab-vmjw (Rybrevant) plus lazertinib (Lazcluze) significantly improved overall survival (OS) vs osimertinib (Tagrisso) when used as frontline treatment in patients with EGFR-mutant non–small cell lung cancer (NSCLC), according to updated data from the phase 3 MARIPOSA trial (NCT04487080) presented during the 2025 European Lung Cancer Congress.1
At a median follow-up of 37.8 months, the median OS with the doublet (n = 429) was not reached (NR; 95% CI, 42.9-NR) vs 36.7 months (95% CI, 33.4-41.0) with osimertinib (n = 429), translating to a 25% reduction in the risk of death (HR, 0.75; 95% CI, 0.61-0.92; P < .005). The OS curves continued to widen, with a projected median OS benefit of greater than 1 year. The 36-month OS rates with the combination vs osimertinib were 60% and 51%, respectively; at 42 months, these rates were 56% and 44%.
“Patients live longer with first-line amivantamab plus lazertinib, with MARIPOSA demonstrating practice-changing superior OS vs osimertinib and potentially extending median survival beyond 4 years,” James Chih-Hsin Yang, MD, PhD, of National Taiwan University Cancer Center, National Taiwan University Hospital, in Taipei, Taiwan, said in a presentation of the data.
Making Sense of MARIPOSA: Refresh of Trial Design, Population, and Key Objectives
The pivotal phase 3 study enrolled patients with treatment-naive, locally advanced or metastatic NSCLC who had documented EGFR exon 19 deletion or L858R and an ECOG performance status no higher than 1. Study participants (n = 1074) were randomly assigned 2:2:1 to 1 of 3 arms: amivantamab plus lazertinib (open-label), osimertinib (blinded), or lazertinib monotherapy (blinded). The third arm was included to evaluate the contribution of components. Stratification factors included EGFR mutation type (exon 19 deletion vs L858R), Asian race (yes vs no), and history of brain metastases (yes vs no).
The primary end point of the study was progression-free survival (PFS) by blinded independent central review (BICR) and RECIST v1.1 criteria. Earlier data from the study showed that the doublet reduced the risk of disease progression or death by 30% vs osimertinib (HR, 0.70; 95% CI, 0.58-0.85; P < .001).2 The median PFS with the combination was 23.7 months vs 16.6 months with osimertinib. These findings supported the FDA’s decision to approve the amivantamab plus lazertinib for this population in August 2024.3
A key secondary end point of the study was protocol-specified final OS, which is what the current presentation focused on.1 Other end points reported on at the meeting included intracranial PFS (icPFS), intracranial overall response rate (icORR), intracranial duration of response (icDOR), time to symptomatic progression (TTSP), and safety.
“OS was tested with a 2-sided alpha of 0.05, determined by O’Brien-Fleming alpha spending approach as implemented by the Lan-DeMets method,” Yang noted.
Diving Into the Latest Data
Of the total 1074 patients who underwent randomization, 858 patients were randomized to the doublet or osimertinib. A total of 421 patients ended up receiving amivantamab/lazertinib and 260 of them ended up discontinuing treatment. The most common reason for doing so was disease progression (33%). A total of 428 patients ended up receiving osimertinib and 310 discontinued the monotherapy. Again, the most common reason for discontinuation was disease progression (55%).
Baseline characteristics were well balanced across the treatment arms. The median patient age was 63.5 years (range, 25-88), more than half were female (doublet, 64%; osimertinib, 59%) and Asian (58%; 59%), and most had an ECOG performance status of 1 (67% vs 65%). About one-third of patients in both arms had a history of smoking and about 40.5% of patients had a history of brain metastases. Sixty percent of patients in both arms had EGFR exon 19 deletion and the remaining 40% in both arms had EGFR L858R. Almost all (97%) had adenocarcinoma subtype.
A generally consistent OS benefit was observed with the doublet vs osimertinib in predefined subgroups, with the exception of those aged 65 years or older (HR, 1.11; 95% CI, 0.84-1.48). Seventy-four percent of patients received second-line treatment, suggestive that a long-term treatment plan after frontline treatment with amivantamab/lazertinib is feasible, according to Yang. The most common subsequent therapy class was chemotherapy-based regimens for both arms. Notably, the trial did not permit crossover.
The doublet provided a longer icPFS than osimertinib, at median of 25.4 months (95% CI, 20.1-29.5) vs 22.2 months (95% CI, 18.4-26.9), respectively (HR, 0.79; 95% CI, 0.61-1.02; P = .07). The 3-year landmark icPFS rates in the respective arms were 36% and 18%. The doublet also showcased greater durability of response than osimertinib, with improved icDOR. The icORR achieved with amivantamab plus lazertinib was 78% (95% CI, 71%-84%) vs 77% (95% CI, 71%-83%) with osimertinib, and the median icDOR in the respective arms was 35.7 months (95% CI, 25.8-NR) and 29.6 months (95% CI, 23.9-34.1).
Moreover, the doublet continues to significantly delay the time to onset or worsening of lung cancer symptoms by a median of greater than 14 months, Yang added. The median TTSP with the combination was 43.6 months (95% CI, 36.0-NR) vs 29.3 months (95% CI, 26.4-33.4) with osimertinib (HR, 0.69; 95% CI, 0.57-0.83; P < .001).
Safety Spotlight
The median duration of treatment for the doublet was 27.0 months vs 22.4 months with osimertinib. The toxicity profile of the combination was aligned with previous reports. The majority of the toxicities experienced with the doublet were related to EGFR or MET inhibition and were grade 1 or 2 in severity. Twenty-one percent of patients received antibiotics for rash at the start of the study. At baseline, 5% of patients were on anticoagulation; venous thromboembolic events (VTEs) occurred in 40% of those who received the doublet and 11% of those who were given osimertinib monotherapy. Notably, most first-onset AES occurred early, between 0 to 4 months. Longer-term follow-up did not reveal any new safety signals indicative that long-term treatment with the combination is feasible.
Moreover, Yang noted that early onset AEs can significantly be reduced by leveraging prophylactic strategies. For example, the COCOON DM regimen led to an approximate 2-fold reduction in grade 2 or higher dermatologic toxicities, the SKIPPirr regimen led to an approximate 3-fold reduction infusion-related reactions, and prophylactic anticoagulation led to an approximate 2-fold reduction in VTEs.
Disclosures: Dr Yang disclosed serving in a consulting or advisory role for Boehringer Ingelheim, Novartis, AstraZeneca, Clovis Oncology, MSD Oncology, Celgene, Bayer, Pfizer, Ono Pharmaceutical, Bristol Myers Squibb, Yuhan, Hansoh, Blueprint Medicines, Daiichi Sankyo, G1 Therapeutics, AbbVie, Takeda, Amgen, Incyte, Eli Lilly, GlaxoSmithKline, Merck KGaA, Daiichi Sankyo/AstraZeneca, Puma Biotechnology, Gilead Sciences, Taiho Pharmaceutical, Bayer, Roche/Genentech, Sanofi, and ArriVent Biopharma. He received honoraria from Boehringer Ingelheim, Roche, Merck Sharp & Dohme, AstraZeneca, Novartis, Bristol Myers Squibb, Ono Pharmaceutical, Takeda, Eil Lilly, Pfizer, Amgen, AstraZeneca/MedImmune, Dizal Pharma, Tahio Pharmaceutical, Roche/Genentech, Daiichi Sankyo/AstraZeneca, MSD Oncology, BeiGene, Gilead Sciences, and Sanofi/Regeneron. Travel, accommodation, and expenses were provided by Pfizer, AstraZeneca, and Dizal Pharma. Research funding was provided by AstraZeneca.
References
Yang JC-H, Kim YJ, Lee S-H, et al. Amivantamab plus lazertinib vs osimertinib in first-line EGFR-mutant advanced NSCLC. Presented at: 2025 European Lung Cancer Congress; March 26-29, 2025; Paris, France. Abstract 4O.
Cho BC, Lu S, Felip E, et al. Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC. N Engl J Med. 2024;391(16):1486-1498. doi:10.1056/NEJMoa2403614
Rybrevant (amivantamab-vmjw) plus Lazcluze (lazertinib) approved in the U.S. as a first-line chemotherapy-free treatment for patients with EGFR-mutated advanced lung cancer. News release. Johnson & Johnson. August 20, 2024. Accessed March 26, 2025. https://www.investor.jnj.com/news/news-details/2024/RYBREVANT-amivantamab-vmjw-plus-LAZCLUZE-lazertinib-approved-in-the-U.S.-as-a-first-line-chemotherapy-free-treatment-for-patients-with-EGFR-mutated-advanced-lung-cancer/default.aspx