Dirk Arnold, MD, PhD, Director of the Asklepios Tumorzentrum Hamburg, discusses results from the OrigAMI-1 clinical trial in left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC).
Approximately 50% of patients diagnosed with colorectal cancer have wild-type KRAS, NRAS, and BRAF genes. Standard of care therapy for these patients is doublet chemotherapy (FOLFOX or FOLFORI) combined with anti-EGFR therapy, but resistance is common. Amivantamab is an EGFR-MET bispecific antibody being evaluated in combination with FOLFOX or FOLFORI in patients with RAS/BRAF wild-type mCRC.
OriGAMI-1
OrigAMI-1 was a phase 1b/2, open-label study of amivantamab monotherapy and in addition to standard-of-care chemotherapy in participants with advanced or metastatic colorectal cancer. Amivanatamab is an EGFR-MET bispecific antibody. Patients were divided into three cohorts; patients with left-sided mCRC without prior anti-EGFR therapy (cohort A), patients with left-sided mCRC with prior anti-EGFR therapy (cohort B), and patients with right-sided mCRC (cohort C).
Results illustrated high baseline mRNA expression of AREG and EREG ligands associated with treatment across all cohorts. In cohort A, media progression-free survival was significantly longer for patients with high AREG expression versus low.
Differential expression analyses after treatment showed significant changes in over 800 genes across all cohorts. The EGFR pathway was significantly downregulated following treatment and pathway enrichment analyses identified significant enrichment of cell cycle and natural killer cell-mediated cytotoxicity pathways.
The cell cycle pathway score was significantly downregulated following treatment, implying reduced cell proliferation. A significant upregulation of dendritic cell and T-cell–inflamed signature scores was observed with treatment, potentially implying increased immune cell infiltration of the tumor microenvironment. Amivanatamab also increased the cytolytic and NK cell–mediated cytotoxicity pathway scores, implying an increase in cytotoxic immune cells.
OriGAMI-2
The OrigAMI-2 study (NCT06662786) is an ongoing, randomized, multicenter, global, phase 3 clinical trial that will continue evaluating the efficacy of amivantamab versus cetuximab, both in combination with FOLFOX or FOLFORI, as a first-line treatment in left-sided RAS/BRAF wild-type mCRC.
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