{"entity":{"id":"paper-mariposa-nejm-2024","kind":"paper","name":"MARIPOSA: amivantamab plus lazertinib versus osimertinib as first treatment for EGFR-mutated lung cancer","aka":[],"tldr":"Combining an EGFR-MET bispecific antibody with a third-generation EGFR pill beat osimertinib alone, delaying progression by about seven months and later improving survival, at the cost of more side effects.","summary":"Phase 3 trial of 1,074 patients with untreated EGFR-mutated (exon 19 deletion or L858R) advanced NSCLC, randomised 2:2:1 to amivantamab plus lazertinib, osimertinib, or lazertinib alone. Primary endpoint was PFS by blinded review for the combination versus osimertinib.\n\nMedian PFS was 23.7 vs 16.6 months (HR 0.70). A 2025 final overall survival analysis reported a significant improvement (HR about 0.75) with median survival in the combination arm not reached and projected to exceed osimertinib by more than a year. It is the first regimen to beat osimertinib on survival, but adds infusion reactions, venous thromboembolism, rash and paronychia.","asOf":"2026-09-08","links":[{"label":"NEJM 2024","url":"https://doi.org/10.1056/NEJMoa2403614"},{"label":"ClinicalTrials.gov NCT04487080","url":"https://clinicaltrials.gov/study/NCT04487080"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/38924756/"}],"tags":[],"related":["paper-planchard-flaura2-osimertinib-chemotherapy-nejm-2023","paper-flaura-nejm-2018","paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011"],"cancers":["nsclc","lung-cancer","egfr-mutant-nsclc"],"sections":["targeted-therapy"],"technologies":["bispecific-antibody","kinase-inhibitors"],"targets":["egfr","met"],"drugs":["amivantamab","osimertinib","lazertinib"],"companies":["johnson-johnson"],"institutions":["severance"],"pathways":[],"terms":["pfs","os","resistance","first-line","ctdna","driver-mutation"],"trials":["mariposa","flaura2"],"people":["cho-byoung-chul","lu-shun","enriqueta-felip","lee-se-hoon","benjamin-besse","prabhash-kumar"],"bottlenecks":["b-resistance","b-toxicity-qol","b-drug-pricing","b-combination-space"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2024,"doi":"10.1056/NEJMoa2403614","pmid":"38924756","authors":"Cho BC, Lu S, Felip E, et al.","paperType":"rct","findings":["Median PFS 23.7 vs 16.6 months; HR 0.70 (95% CI 0.58-0.85).","Overall survival at final analysis (2025): HR about 0.75; median not reached vs 36.7 months for osimertinib.","Benefit was seen in high-risk subgroups (TP53 co-mutation, detectable ctDNA, brain or liver metastases).","Grade 3 or higher adverse events 75% vs 43%; venous thromboembolism about 37% vs 9%, prompting prophylactic anticoagulation in the first four months.","Lazertinib alone performed similarly to osimertinib."],"whatItMeans":"Patients newly diagnosed with EGFR-mutated advanced lung cancer now have a first-line option that improves survival over osimertinib, particularly if they have high-risk features. The trade-off is intravenous (now subcutaneous) infusions and considerably more skin, nail and clotting toxicity, so osimertinib alone remains reasonable for those who prioritise convenience and tolerability. Both this regimen and osimertinib plus chemotherapy (FLAURA2) are approved; there is no direct comparison.","caveats":["Toxicity is substantially higher and treatment is more burdensome than an oral tablet alone.","No head-to-head comparison with osimertinib plus chemotherapy.","Cost is very high and access outside wealthy countries is limited.","Whether resistance mechanisms after the combination are more treatable than after osimertinib is unknown."],"changedPractice":true,"participants":1074},"route":"/key-papers/paper-mariposa-nejm-2024/","neighbours":{"paper":[{"id":"paper-wolf-geometry-mono-1-capmatinib-nejm-2020","kind":"paper","name":"Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer","route":"/key-papers/paper-wolf-geometry-mono-1-capmatinib-nejm-2020/"},{"id":"paper-flaura-nejm-2018","kind":"paper","name":"FLAURA: osimertinib as first treatment for EGFR-mutated lung cancer","route":"/key-papers/paper-flaura-nejm-2018/"},{"id":"paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011","kind":"paper","name":"Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors","route":"/key-papers/paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011/"},{"id":"paper-planchard-flaura2-osimertinib-chemotherapy-nejm-2023","kind":"paper","name":"Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC","route":"/key-papers/paper-planchard-flaura2-osimertinib-chemotherapy-nejm-2023/"}],"cancer":[{"id":"egfr-mutant-nsclc","kind":"cancer","name":"EGFR-mutated non-small-cell lung cancer","route":"/cancers/egfr-mutant-nsclc/"},{"id":"lung-cancer","kind":"cancer","name":"Lung cancer (all types)","route":"/cancers/lung-cancer/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"section":[{"id":"targeted-therapy","kind":"section","name":"Targeted Therapy","route":"/fronts/targeted-therapy/"}],"technology":[{"id":"bispecific-antibody","kind":"technology","name":"Bispecific antibodies","route":"/technologies/bispecific-antibody/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"target":[{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"met","kind":"target","name":"MET","route":"/targets/met/"}],"drug":[{"id":"amivantamab","kind":"drug","name":"Amivantamab","route":"/drugs/amivantamab/"},{"id":"lazertinib","kind":"drug","name":"Lazertinib","route":"/drugs/lazertinib/"},{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"}],"company":[{"id":"johnson-johnson","kind":"company","name":"Johnson & Johnson","route":"/companies/johnson-johnson/"}],"institution":[{"id":"severance","kind":"institution","name":"Severance Hospital, Yonsei University","route":"/institutions/severance/"}],"term":[{"id":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/"},{"id":"driver-mutation","kind":"term","name":"Driver mutation","route":"/terms/driver-mutation/"},{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"},{"id":"first-line","kind":"term","name":"Lines of therapy","route":"/terms/first-line/"},{"id":"os","kind":"term","name":"Overall survival (OS)","route":"/terms/os/"},{"id":"pfs","kind":"term","name":"Progression-free survival (PFS)","route":"/terms/pfs/"}],"trial":[{"id":"flaura2","kind":"trial","name":"FLAURA2","route":"/trials/flaura2/"},{"id":"mariposa","kind":"trial","name":"MARIPOSA","route":"/trials/mariposa/"}],"person":[{"id":"benjamin-besse","kind":"person","name":"Benjamin Besse","route":"/people/benjamin-besse/"},{"id":"cho-byoung-chul","kind":"person","name":"Byoung Chul Cho","route":"/people/cho-byoung-chul/"},{"id":"enriqueta-felip","kind":"person","name":"Enriqueta Felip","route":"/people/enriqueta-felip/"},{"id":"prabhash-kumar","kind":"person","name":"Kumar Prabhash","route":"/people/prabhash-kumar/"},{"id":"lee-se-hoon","kind":"person","name":"Se-Hoon Lee","route":"/people/lee-se-hoon/"},{"id":"lu-shun","kind":"person","name":"Shun Lu","route":"/people/lu-shun/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-drug-pricing","kind":"bottleneck","name":"Prices and value","route":"/bottlenecks/b-drug-pricing/"},{"id":"b-combination-space","kind":"bottleneck","name":"Too many combinations to test","route":"/bottlenecks/b-combination-space/"},{"id":"b-toxicity-qol","kind":"bottleneck","name":"Toxicity and quality of life are undervalued","route":"/bottlenecks/b-toxicity-qol/"}],"journal":[{"id":"nejm","kind":"journal","name":"New England Journal of Medicine","route":"/journals/nejm/"}],"roadmap":[{"id":"lung-cancer-evidence-roadmap","kind":"roadmap","name":"Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch","route":"/roadmaps/lung-cancer-evidence-roadmap/"}],"idea":[{"id":"idea-lung-resistance-directed-sequencing-at-every-progression","kind":"idea","name":"Make resistance a diagnosis: sequence at every progression and choose the next line from what the tumour became","route":"/ideas/idea-lung-resistance-directed-sequencing-at-every-progression/"},{"id":"idea-tr2-alternating-vs-concurrent","kind":"idea","name":"Test alternating drug schedules against giving both drugs at once","route":"/ideas/idea-tr2-alternating-vs-concurrent/"}]}}