Background
Phase III, open-label, randomized controlled trial (MARIPOSA). N=858 (Asian subset analysis) patients with EGFR-mutant (exon 19 del or L858R) treatment-naive advanced NSCLC. Tested chemotherapy-free dual EGFR/MET-directed therapy vs standard third-generation TKI in first line.
Interventions and follow up
Arm A: Amivantamab 1050 mg (1400 mg if ≥80 kg) IV weekly cycle 1 then q2wk + lazertinib 240 mg PO once daily
Arm B: Osimertinib 80 mg PO once daily
Primary endpoint: PFS
mFollow up: 37.8 months (OS analysis)
Arm B: Osimertinib 80 mg PO once daily
Primary endpoint: PFS
mFollow up: 37.8 months (OS analysis)
Results
PFS: 18.2 vs 12.9 mo, HR 0.65, 95% CI 0.48-0.87, P=.003
OS: not reached vs 36.7 mo, HR 0.75, 95% CI 0.61-0.92, P<.005
ORR: 86% vs 85%
OS: not reached vs 36.7 mo, HR 0.75, 95% CI 0.61-0.92, P<.005
ORR: 86% vs 85%
Adverse events
Dermatologic: rash 86%, nail toxicity 71%, dry skin 25%, pruritus 24%
Infusion/vascular: infusion-related reactions 63%, VTE 36%, hemorrhage 25%
Gastrointestinal: stomatitis 43%, diarrhea 31%, constipation 29%, decreased appetite 24%, nausea 21%
Musculoskeletal/neuro: musculoskeletal pain 47%, paresthesia 35%
Other: edema 43%, fatigue 32%, ocular toxicity 16%
Infusion/vascular: infusion-related reactions 63%, VTE 36%, hemorrhage 25%
Gastrointestinal: stomatitis 43%, diarrhea 31%, constipation 29%, decreased appetite 24%, nausea 21%
Musculoskeletal/neuro: musculoskeletal pain 47%, paresthesia 35%
Other: edema 43%, fatigue 32%, ocular toxicity 16%
Conclusions
Amivantamab-lazertinib is the first chemotherapy-free regimen to improve OS over osimertinib in first-line EGFR-mutant advanced NSCLC, supporting its role as a new first-line standard of care.
Key Limitations
Substantially higher toxicity than osimertinib monotherapy (rash, nail, VTE, infusion reactions), requiring prophylaxis and IV access. Open-label design. VTE risk prompts consideration of prophylactic anticoagulation. Increased treatment burden (weekly then q2wk IV infusions) vs oral osimertinib. Lazertinib monotherapy arm reported separately.
Clinical Context
FDA approved amivantamab + lazertinib for first-line EGFR exon 19 del/L858R advanced NSCLC; EMA approved. ASCO and ESMO recognize it as a first-line option, with osimertinib monotherapy and osimertinib + chemotherapy (FLAURA2) as alternatives. Choice balances OS benefit against added toxicity, VTE risk, and infusion burden.