Background
Phase III MARIPOSA-2 trial; N=657 EGFR-mutant NSCLC after progression on osimertinib; open-label, 3-arm. Evaluated adding amivantamab (EGFR-MET bispecific) to platinum chemotherapy ± lazertinib.
Interventions and follow up
Arm A: Amivantamab + lazertinib + chemotherapy ×4 cycles, then amivantamab + pemetrexed maintenance
Arm B: Amivantamab + chemotherapy ×4 cycles, then amivantamab + pemetrexed maintenance
Arm C: Carboplatin + pemetrexed ×4 cycles, then pemetrexed maintenance (placebo infusion)
Primary endpoint: PFS
mFollow up: ~9.5mo
Arm B: Amivantamab + chemotherapy ×4 cycles, then amivantamab + pemetrexed maintenance
Arm C: Carboplatin + pemetrexed ×4 cycles, then pemetrexed maintenance (placebo infusion)
Primary endpoint: PFS
mFollow up: ~9.5mo
Results
mPFS: 8.3 (ami+laz+chemo) vs 6.3 (ami+chemo) vs 4.2mo (chemo); HR 0.44 and 0.48 vs chemo, P<.001
mOS HR: 0.77, 95% CI 0.49–1.21 (ami+chemo vs chemo)
mOS HR: 0.96, 95% CI 0.67–1.35 (ami+laz+chemo vs chemo)
ORR: 64% vs 63% vs 36%
Median intracranial PFS: 12.8 vs 12.5 vs 8.3mo; HR 0.55 and 0.58 vs chemo
mOS HR: 0.77, 95% CI 0.49–1.21 (ami+chemo vs chemo)
mOS HR: 0.96, 95% CI 0.67–1.35 (ami+laz+chemo vs chemo)
ORR: 64% vs 63% vs 36%
Median intracranial PFS: 12.8 vs 12.5 vs 8.3mo; HR 0.55 and 0.58 vs chemo
Adverse events
Dermatologic: rash (any grade) ~30% vs 0% (amivantamab arms higher).
Infusion: infusion-related reactions 19% vs 0%.
Overall: Grade ≥3 AEs 40% vs 37% (comparable); hematologic chemo toxicities similar across arms.
Infusion: infusion-related reactions 19% vs 0%.
Overall: Grade ≥3 AEs 40% vs 37% (comparable); hematologic chemo toxicities similar across arms.
Conclusions
Adding amivantamab to chemotherapy after osimertinib progression significantly prolonged PFS and nearly doubled response rates, establishing a new second-line standard. OS data were immature; rash and infusion reactions require management.
Key Limitations
Open-label; OS immature/not significant; adding lazertinib increased toxicity without clear PFS gain over ami+chemo; short follow-up.
Clinical Context
Amivantamab + chemotherapy is FDA-approved for EGFR-mutant NSCLC after osimertinib failure. ESMO recognizes amivantamab + platinum chemo as a preferred second-line option post-osimertinib; ami+chemo (without lazertinib) optimizes the toxicity/benefit balance. Dosing: amivantamab 1400/1750 mg IV (≥80 kg) QW ×4 then Q3W; carboplatin AUC5 ×4; pemetrexed 500 mg/m² until progression.