P76.74 PAPILLON: Randomized Phase 3 Study of Amivantamab Plus Chemotherapy vs Chemotherapy Alone in EGFR Exon20ins NSCLC

Abstract

Epidermal growth factor receptor (EGFR) Exon 20 insertions (Exon20ins) account for approximately 10% of all EGFR-mutant non-small cell lung cancers (NSCLCs). Currently approved EGFR tyrosine kinase inhibitors (TKIs) are considered ineffective against Exon20ins NSCLC, and the standard of care for patients with Exon20ins disease remains platinum-based doublet chemotherapy. Amivantamab (JNJ-61186372) is an EGFR-MET bispecific antibody with immune-cell directing activity that targets activating and resistance EGFR mutations and MET mutations and amplifications. Amivantamab has shown monotherapy activity, with a tolerable safety profile, in the ongoing phase 1 CHRYSALIS study (NCT02609776) in patients with diverse EGFR-mutant NSCLC and has received FDA Breakthrough Therapy Designation for the treatment of patients with EGFR Exon20ins NSCLC, after prior platinum-based chemotherapy (Haura JCO 37;no.15_suppl:9009; Park JTO 38;no. 15_suppl:9512). The primary objective of this phase 3 randomized, open-label study is to compare the efficacy of amivantamab in combination with chemotherapy (amivantamab/carboplatin/pemetrexed) versus carboplatin/pemetrexed alone as a first-line treatment for patients with EGFR Exon20ins disease. The multicenter, global PAPILLON study is planned to open in 200 sites in 25 countries and enroll patients with EGFR Exon20ins-mutant NSCLC who are treatment-naive for metastatic disease, although limited prior EGFR TKI exposure may be allowed. Eligible patients also have measurable disease according to RECIST v1.1, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 – 1, and adequate bone marrow and organ function. Additionally, patients with history of brain metastases are eligible provided they have been definitively treated, are asymptomatic, and clinically stable. Approximately 300 patients will be randomly assigned 1:1 to receive amivantamab/carboplatin/pemetrexed (Arm A) or carboplatin/pemetrexed (Arm B). Randomization will be stratified by ECOG PS (0 or 1), history of brain metastases (yes or no), and prior EGFR TKI (yes or no). Patients in Arm A will be treated with amivantamab/carboplatin/pemetrexed in a 21-day cycle for 4 cycles followed by maintenance with amivantamab and pemetrexed until disease progression or any of the treatment discontinuation criterion is met. Similarly, patients in Arm B will receive treatment with carboplatin/pemetrexed in a 21-day cycle for 4 cycles followed by maintenance therapy with pemetrexed alone. Crossover from the chemotherapy arm to monotherapy amivantamab may be allowed. The primary endpoint of the study is progression-free survival (PFS) as assessed by blinded independent central review according to RECIST v1.1. Key secondary endpoints include objective response rate and overall survival. Safety assessments will include monitoring adverse events and laboratory abnormalities. Exon20ins, amivantamab, chemotherapy