Amivantamab treatment and intra-tumoral gene expression and immune cell changes in refractory metastatic colorectal cancer (mCRC): Whole transcriptome RNA-sequencing analysis from the OrigAMI-1 study.
Authors: Cathy Eng, Paul Eliezer Oberstein, Joel R. Hecht, Filippo Pietrantonio, Dirk Arnold, Yong Sang Hong, Myung Ah Lee, Harvey Yu-Li Su, Sae-Won Han, Rianka Bhattacharya, Emrullah Yilmaz, Mahesh Kumar Daksh, Mahadi Baig, Sanjib Chowdhury, Xuesong Lu, Joshua C. Curtin, Medha Kamat, Michael Gormley, Bharvin Patel, Elena Elez
Journal: Journal of Clinical Oncology (2025)

3550 Background: Amivantamab (ami) is an FDA- and EMA-approved EGFR-MET bispecific antibody with immune cell–directing activity for EGFR -mutated advanced non-small cell lung cancer. Ami monotherapy has shown promising activity in participants (pts) with refractory mCRC, independent of primary tumor sidedness (left- or right-sided). Here, we analyzed gene expression data from the OrigAMI-1 study to identify mechanisms of sensitivity and action in response to ami monotherapy. Methods: The phase 1b/2 OrigAMI-1 study (NCT05379595) enrolled pts with mCRC harboring wild-type KRAS , NRAS , BRAF , and EGFR ectodomain, without ERBB2 / HER2 amplification. Pts with left-sided mCRC without prior anti-EGFR therapy (Cohort A) and with prior anti-EGFR therapy (Cohort B), as well as pts with right-sided mCRC (Cohort C) received intravenous ami monotherapy (1050 mg; ≥80 kg: 1400 mg). Tumor biopsy samples were collected at screening and Cycle 3 Day 1 (C3D1; if feasible). Whole transcriptome RNA-sequencing data of paired baseline and C3D1 tumor samples were generated by Foundation Medicine. Gene expression data were analyzed using standard bioinformatic methods to identify gene signatures associated with ami treatment in baseline tumor samples (n = 76) and paired baseline and C3D1 tumor samples (n = 17). Results: High baseline mRNA expression of AREG and EREG ligands was associated with treatment response across all cohorts (n = 76). In Cohort A (n = 16), median progression-free survival was significantly longer for pts with high (n = 8) vs low (n = 8) AREG expression (9.1 mo vs 4.5 mo, respectively; P &lt; 0.01). Differential expression analyses after ami treatment showed significant changes in &gt; 800 genes ( P &lt; 0.01) across all cohorts (n = 17). The EGFR pathway was significantly downregulated after ami treatment ( P &lt; 0.01). Pathway enrichment analyses identified significant enrichment of cell cycle and natural killer (NK) cell–mediated cytotoxicity pathways. The cell cycle pathway score was significantly downregulated following ami treatment ( P &lt; 0.01), implying reduced cell proliferation. A significant upregulation of dendritic cell ( P &lt; 0.005) and T-cell–inflamed signature scores ( P &lt; 0.05) was observed with ami treatment, potentially implying increased immune cell infiltration of the tumor microenvironment. Ami also increased the cytolytic ( P &lt; 0.05) and NK cell–mediated cytotoxicity pathway scores ( P &lt; 0.05), implying an increase in cytotoxic immune cells. Additional biomarker analyses are ongoing and will be presented at the meeting. Conclusions: Amivantamab downregulates EGFR and cell cycle pathways and increases cytotoxic immune cell signatures consistent with immune cell infiltration into tumors. Elevated AREG and EREG ligand expression correlated with response in wild-type refractory mCRC. Clinical trial information: NCT05379595 .