Background
Phase 3 global RCT (PAPILLON); N=308 treatment-naive advanced NSCLC with EGFR exon 20 insertion mutations.
Interventions and follow up
Arm A: Amivantamab + carboplatin/pemetrexed (amivantamab 1400 mg, 1750 mg if ≥80 kg, weekly x4 wks then q3w from cycle 3 at 1750/2100 mg)
Arm B: Carboplatin AUC5 x4 cycles + pemetrexed 500 mg/m2 q3w until progression
Primary endpoint: PFS by blinded independent central review
mFollow up: 14.9mo
Arm B: Carboplatin AUC5 x4 cycles + pemetrexed 500 mg/m2 q3w until progression
Primary endpoint: PFS by blinded independent central review
mFollow up: 14.9mo
Results
mPFS: 11.4mo vs 6.7mo, HR 0.40, 95%CI 0.30-0.53, P<.001
OS (interim): NR vs NR, HR 0.67, 95%CI 0.42-1.09, P=.11
ORR: 73% vs 47%
OS (interim): NR vs NR, HR 0.67, 95%CI 0.42-1.09, P=.11
ORR: 73% vs 47%
Adverse events
Hematologic: neutropenia 59% vs 45%; anemia 50% vs 55%; febrile neutropenia 3% vs 2%
EGFR/MET-related: paronychia 56% vs NR; rash 54% vs NR
Infusion: infusion-related reactions 42% vs 1%
GI: nausea 36% vs 42%
EGFR/MET-related: paronychia 56% vs NR; rash 54% vs NR
Infusion: infusion-related reactions 42% vs 1%
GI: nausea 36% vs 42%
Conclusions
First-line amivantamab plus chemotherapy markedly prolonged PFS versus chemotherapy alone in EGFR exon 20 insertion NSCLC, establishing a new standard of care.
Key Limitations
OS immature at primary analysis; higher rates of skin/nail and infusion toxicity; no head-to-head against EGFR exon 20 TKIs.
Clinical Context
FDA approved amivantamab + carboplatin/pemetrexed (Rybrevant) for 1L EGFR exon 20 insertion NSCLC March 2024; now preferred 1L regimen for this subset over prior post-platinum amivantamab monotherapy.