Amivantamab in Chemorefractory Metastatic Colorectal Cancer

Clinical Summary: 

• Design/Context: The OrigAMI-1 study evaluated amivantamab monotherapy in patients with chemorefractory RAS/BRAF/EGFR wild-type metastatic colorectal cancer without HER2 amplification.
• Key Outcomes: Amivantamab demonstrated durable responses across multiple cohorts, including patients with prior anti-EGFR exposure and right-sided tumors, with manageable toxicity.
• Clinical Relevance: These findings support dual EGFR/MET targeting as a promising strategy in refractory metastatic colorectal cancer and provide rationale for ongoing phase 3 combination studies.

Paul Oberstein, MD, NYU Langone Health, New York, New York, discusses results from the OrigAMI-1 trial evaluating amivantamab monotherapy in chemorefractory RAS/BRAF wild-type metastatic colorectal cancer (mCRC). 

Results demonstrated durable antitumor activity across left- and right-sided tumors regardless of prior anti-EGFR therapy exposure, with a safety profile consistent with prior NSCLC experience.

Transcript: 

Hello, my name is Paul Oberstein, I’m a GI medical oncologist and the section chief of GI Medical Oncology at NYU Langone Health in New York City. I oversee a GI oncology group and conduct clinical trials.

I’m here today to talk about a trial that we recently published called the OrigAMI-1 trial. This is a trial of amivantamab in RAS/BRAF wild-type relapsed metastatic colorectal cancer. The trial evaluated a novel therapy called amivantamab, which is a bispecific antibody targeting both EGFR and MET in colon cancer patients.

Amivantamab is thought to provide benefit by targeting EGFR, which is a known target in colon cancer, as well as MET, which is frequently overexpressed in this disease. In preclinical work, there is also evidence that this bispecific antibody contributes to an immune response. In this clinical trial, we evaluated the role of amivantamab monotherapy in 3 different cohorts of patients with colon cancer.

In one group, we tested amivantamab in patients with metastatic or recurrent colon cancer that was refractory to prior therapy, located on the left side of the colon, and who had not previously received an EGFR antibody. We also looked at another cohort of patients with left-sided colon cancer who had previously received an EGFR antibody. We evaluated a third cohort of patients with right-sided colon cancer.

The results of the trial showed that in all 3 groups there were responses to amivantamab. Responses were highest in patients with left-sided colon cancer who had not previously received EGFR antibody therapy. However, we also observed responses in patients who had prior EGFR exposure and, somewhat surprisingly, in patients with right-sided colon cancer, where we traditionally would not expect EGFR-targeted therapies to work as well.

Overall, in the left-sided cohorts, the objective response rate was 29% in patients without prior EGFR antibody exposure and 19% in those with prior EGFR therapy. In the right-sided cohort, the response rate was 22%. The median duration of response ranged from about 6 to nearly 10 months across cohorts, and progression-free survival ranged from approximately 3.7 to 5.7 months.

Correlative studies from the trial also identified certain patient populations who appeared more likely to benefit, including patients with high expression of AREG or EREG, which are EGFR ligands associated with greater response to this bispecific EGFR-MET antibody.

Overall, the study demonstrated efficacy in patients with advanced KRAS wild-type colorectal cancer across multiple clinical subgroups. This is an early-phase study, and there are ongoing phase 3 trials evaluating amivantamab in combination with chemotherapy in both first-line and second-line colorectal cancer. We also hope there will be further trials specifically evaluating amivantamab in right-sided KRAS wild-type colon cancer patients.

Our hope is that this therapy may ultimately have relevance for a broad group of patients with colorectal cancer, and this is now being tested in later-phase clinical trials. We look forward to learning more about the efficacy of this medication moving forward.

Source: 

Oberstein PE, Hecht JR, Raghav K, et al. Amivantamab monotherapy in chemorefractory RAS/BRAF wild-type metastatic colorectal cancer: Results from OrigAMI-1, an open-label, phase Ib/II study. J Clin Oncol. Published online:April 21, 2026. doi:10.1200/JCO-25-02187