Antitumor activity of amivantamab by consensus molecular subtypes in <i>RAS</i> / <i>BRAF</i> wild-type metastatic colorectal cancer: Secondary analyses from the phase 1b/2 OrigAMI-1 study.

3548 Background: Colorectal tumors are classified by mutational subtypes and sidedness, which inform treatment and outcomes. They can also be classified into four Consensus Molecular Subtypes (CMS1–4), with CMS2 ( EGFR -dependent, canonical) typically showing better prognosis and CMS4 ( EGFR -independent, MET pathway associated, mesenchymal) associated with poor prognosis and limited response to traditional EGFR inhibition (Thanki Int Biol Biomed J 2017, Woolston Cancer Cell 2019). In prior analyses, cetuximab monotherapy demonstrated greater antitumor activity against CMS2 RAS wild-type (WT) vs CMS4 RAS WT tumors (disease control rate [DCR]: 68% vs 29%; Chowdhury JCO Precis Oncol 2023), suggesting CMS4 may limit cetuximab efficacy de novo. Additionally, CMS2 to CMS4 subtype switching has been described as a cetuximab monotherapy resistance mechanism (Woolston Cancer Cell 2019). Amivantamab, an EGFR–MET bispecific antibody approved for EGFR -mutated NSCLC, has demonstrated antitumor activity in refractory metastatic colorectal cancer (mCRC), independent of sidedness. Given the role of MET in mesenchymal subtypes (CMS4), targeting with amivantamab could demonstrate antitumor activity in both CMS2 and CMS4. Methods: OrigAMI-1 (NCT05379595) enrolled participants with mCRC harboring WT KRAS , NRAS , BRAF , and EGFR ectodomain and without ERBB2 / HER2 amplification. Participants with left-sided mCRC without (Cohort A) or with prior anti-EGFR therapy (Cohort B), and those with right-sided disease (Cohort C), received intravenous amivantamab monotherapy. All enrolled participants had 2–3 prior lines of therapy in the metastatic setting. CMS assignment and expression changes in key EGFR/MET ligands at baseline (n = 76) and Cycle 3 Day 1 (C3D1; n = 17) were analyzed by whole-transcriptome RNA-sequencing of biopsies. Results: CMS2 (canonical) and CMS4 (mesenchymal) comprised ~95% of tumors. Clinical outcomes for CMS2 (n = 42) and CMS4 (n = 31) were comparable: median PFS was 4.2 vs 5.3 months ( P = 0.5), respectively, and median OS was 11.3 vs 13.5 months ( P = 0.6). PFS and OS within CMS2 and CMS4 subgroups remained consistent across sidedness. Overall response rate and DCR were comparable between CMS2 and CMS4 (26% vs 16% and 83% vs 74%, respectively). Genomic profiles derived from ctDNA were similar for CMS2 and CMS4; however, baseline AREG / EREG mRNA expression was higher in CMS2. Paired biopsies demonstrated antitumor activity with or without subtype switching at C3D1. Amivantamab treatment generally decreased AREG / EREG and increased HGF expression, independent of subtype or response. Conclusions: Amivantamab monotherapy demonstrated consistent antitumor activity in both canonical, EGFR -dependent (CMS2) and mesenchymal, EGFR -independent (CMS4) tumors unlike traditional EGFR inhibitors in refractory RAS / BRAF WT mCRC. Clinical trial information: NCT05379595 .