Background: EGFR exon20ins-mutated NSCLC is generally refractory to EGFR tyrosine kinase inhibitors (TKIs) and is associated with poor prognosis. Amivantamab (JNJ-61186372) is a novel, fully human anti-EGFR-MET bispecific antibody whose mechanism of action can target both EGFR- and MET-driven disease and has shown monotherapy activity in patients (pts) with diverse EGFR mutant disease characterized by EGFR C797S, T790M, exon20ins, and MET amplification. We present preliminary results of pts with advanced NSCLC harboring exon20ins mutations from CHRYSALIS, an ongoing phase 1 study of amivantamab (NCT02609776). Methods: This study comprises a dose escalation phase in pts with advanced NSCLC and a dose expansion phase in pts with EGFR- and MET-mutated disease. This analysis includes all enrolled pts with exon20ins disease who received the recommended phase 2 dose (RP2D) of 1050 mg (1400 mg, pts ≥80 kg) amivantamab. Response was assessed by investigator per RECIST v1.1. Results: As of 30 Oct 2019, 50 pts with exon20ins mutations had received amivantamab at the RP2D. 39/50 pts were response-evaluable and had ≥2 disease assessments or had discontinued therapy prior to the assessment period; among these pts, 29 had prior platinum-based chemotherapy (PBCT). Median age for response-evaluable pts was 61 y (40–78), 51% were female, and median prior lines was 1 (0–7). In the 50 pts harboring exon20ins mutations treated at the RP2D, the most common adverse events (AEs) reported were rash (72%), infusion related reaction (60%), and paronychia (34%). Additional EGFR-related AEs included stomatitis (16%), pruritus (14%), and diarrhea (6%). Grade ≥3 AEs were reported in 36% of pts; 6% were treatment-related. One grade 3 diarrhea and no grade ≥3 rash was reported. Among the 39 response-evaluable pts, with a median follow-up of 4 months (1–26), the overall response rate (≥partial response [PR]) was 36% (95% CI, 21–53), and 41% (95% CI, 24–61) for the 29 pts who had prior PBCT. The clinical benefit rate (≥PR or stable disease ≥11 weeks) was 67% for response-evaluable pts and 72% for pts who had prior PBCT. Among all 14 responders, median duration of response was 10 months (1–16), with ongoing responses in 9 pts at data cutoff. Median progression-free survival was 8.3 months (95% CI, 3.0–14.8) for response-evaluable pts and 8.6 months (95% CI, 3.7–14.8) for pts who had prior PBCT. Conclusions: Amivantamab demonstrates robust and durable antitumor activity in pts with exon20ins disease, with a manageable safety profile. Clinical trial information: NCT02609776.