The Phase III MARIPOSA trial has delivered compelling evidence for a new standard of care in first-line EGFR-mutated non-small cell lung cancer (NSCLC), with the combination of RYBREVANT (amivantamab-vmjw) and LAZCLUZE (lazertinib) demonstrating superior survival outcomes compared to osimertinib, the current gold standard.
At three years, 61% of patients treated with the RYBREVANT/LAZCLUZE combination remained alive compared to 53% of those receiving osimertinib, representing a hazard ratio of 0.75 favoring the new regimen. Median overall survival for the combination therapy has not yet been reached, while osimertinib achieved a median overall survival of 37.3 months, suggesting a projected 12-month survival advantage for the combination approach.
Enhanced Intracranial Disease Control
The combination therapy demonstrated particularly impressive results in controlling brain metastases, a critical concern in EGFR-mutated NSCLC management. At three years, 38% of patients on RYBREVANT/LAZCLUZE remained progression-free compared to just 18% on osimertinib. This represents a significant advancement given the high prevalence of brain metastases in this patient population and the historically limited efficacy of existing therapies in central nervous system disease.
The regimen also extended time to symptomatic progression by over 14 months compared to standard care, preserving quality of life for patients throughout their treatment journey.
Addressing Resistance Mechanisms
Updated analysis from the MARIPOSA study, presented at the International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer (WCLC), revealed that the combination therapy effectively prevents common EGFR and MET resistance mechanisms that typically limit the effectiveness of third-generation EGFR tyrosine kinase inhibitor monotherapy.
"With a unique mechanism of action, RYBREVANT plus LAZCLUZE delivers unmatched survival benefit in a chemotherapy-free regimen, projected to exceed four years, while also helping to prevent acquired resistance often seen with regimens that rely only on third-generation TKI therapy to target EGFR," said Yusri Elsayed, M.D., M.H.Sc., Ph.D., Global Therapeutic Area Head, Oncology, Johnson & Johnson Innovative Medicine.
Improving Treatment Experience
Johnson & Johnson presented comprehensive data at WCLC 2025 addressing patient experience improvements, including results from the Phase 2 COCOON study demonstrating effective management of dermatologic reactions and the Phase 2 PALOMA-2 study evaluating subcutaneous amivantamab with once-monthly dosing options.
The COCOON study evaluated a readily available, easy-to-use regimen to manage skin-related reactions in patients receiving first-line RYBREVANT plus LAZCLUZE. Meanwhile, PALOMA-2 study results included evaluation of once-monthly subcutaneous amivantamab combined with LAZCLUZE as first-line treatment, as well as subcutaneous amivantamab plus chemotherapy in second-line settings.
"Improving patient outcomes starts with using the best regimen first, and we are committed to helping patients with their day-to-day treatment experience with their medicines," said Henar Hevia, Ph.D., Senior Director, EMEA Therapy Area Head, Oncology, Johnson & Johnson Innovative Medicine.
Market Impact and Regulatory Status
The global EGFR-mutated NSCLC market is forecasted to grow from $15.6 billion in 2025 to $32.8 billion by 2032, driven by rising biomarker testing rates and adoption of targeted therapies. The combination therapy's first-in-class status as a chemotherapy-free regimen with proven survival benefits positions it to capture significant market share.
RYBREVANT in combination with LAZCLUZE is approved in the U.S., Europe and other markets worldwide for first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations. The subcutaneous formulation is approved in Europe for the same indication, with a Biologics License Application submitted to the U.S. FDA.
The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology include amivantamab-vmjw plus lazertinib as a Category 1 recommendation for first-line therapy in patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations.
Safety Profile
In the MARIPOSA trial involving 421 patients, the most common adverse reactions (≥20%) with RYBREVANT plus LAZCLUZE included rash (86%), nail toxicity (71%), infusion-related reactions (63%), musculoskeletal pain (47%), and stomatitis (43%). The combination can cause serious venous thromboembolic events, with VTEs occurring in 36% of patients, predominantly during the first four months of therapy. Prophylactic anticoagulation is recommended for the first four months of treatment.
The therapy represents a paradigm shift in EGFR-mutated NSCLC treatment, offering the potential for extended survival in a chemotherapy-free regimen while addressing key resistance mechanisms that have historically limited treatment durability in this patient population.
