Amivantamab Monotherapy in Chemorefractory RAS / BRAF Wild-Type Metastatic Colorectal Cancer: Results From OrigAMI-1, an Open-Label, Phase Ib/II Study

PURPOSE Amivantamab, an EGFR-MET bispecific antibody with immune cell–directing activity, is approved in non–small cell lung cancer (NSCLC). Effective treatments are limited for chemorefractory metastatic colorectal cancer (mCRC). METHODS OrigAMI-1 (ClinicalTrials.gov identifier: NCT05379595 ) is a phase Ib/II study evaluating amivantamab monotherapy in chemorefractory (2-3 prior lines) mCRC. Participants had centrally confirmed RAS / BRAF / EGFR ectodomain wild-type status, without ERBB2 / HER2 amplification. Participants with left-sided mCRC without (cohort A) or with (cohort B) prior anti-EGFR antibody treatment, or right-sided mCRC (cohort C) regardless of prior anti-EGFR treatment, received intravenous amivantamab 1,050 mg (1,400 mg for ≥80 kg) once every 2 weeks. The primary end point was objective response rate (ORR) per RECIST v1.1. RESULTS By October 31, 2024, 94 participants received amivantamab monotherapy (median follow-up, 11.9 months). The median age was 60 years, and 65% of participants were male, with a median of 2 prior lines (94%, prior bevacizumab). In left-sided cohorts, the ORR was 29% (5 of 17) in cohort A and 19% (10 of 54) in cohort B; the median duration of response (DoR) was 9.0 months and 6.1 months, and the median progression-free survival (PFS) was 5.7 months and 4.6 months, respectively. In the right-sided cohort, the ORR was 22% (10 of 23; 43% had prior anti-EGFR), the median DoR was 9.8 months, and the median PFS was 3.7 months. Most frequent treatment-related grade ≥3 adverse events (AEs) were rash (7%), dermatitis acneiform (4%), and hypoalbuminemia (4%). One participant discontinued amivantamab because of a treatment-related AE. CONCLUSION Amivantamab monotherapy demonstrated promising, durable antitumor activity in chemorefractory mCRC, regardless of prior anti-EGFR therapy and the primary tumor location. The amivantamab safety profile in mCRC is consistent with experience in NSCLC. Amivantamab plus chemotherapy is currently being explored in two phase III studies in first-line and second-line mCRCs.