The bispecific antibody amivantamab-vmjw (Rybrevant) has demonstrated encouraging clinical activity in colorectal cancer, prompting the launch of two phase 3 trials following promising results from the phase 1b/2 OrigAMI-1 study presented at the 2025 Gastrointestinal Cancers Symposium.
Phase 1b/2 Trial Results Show Clinical Activity
In the OrigAMI-1 trial (NCT05379595), patients with advanced or metastatic colorectal cancer treated with amivantamab monotherapy achieved an objective response rate of 22% (95% CI, 8%-44%) at a median follow-up of 8.1 months. The median duration of response reached 9.8 months (95% CI, 3.7-not evaluable), with a disease control rate of 78% (95% CI, 56%-93%) and median progression-free survival of 3.7 months (95% CI, 3.4-5.5) among 23 patients.
The combination of amivantamab with standard chemotherapy regimens FOLFOX or FOLFIRI showed enhanced efficacy in a smaller cohort of seven patients. At a median follow-up of 8.2 months, this combination achieved an objective response rate of 43% (95% CI, 10%-82%), a disease control rate of 86% (95% CI, 42%-100%), and a median progression-free survival of 7.4 months (95% CI, 1.8-not evaluable).
Trifunctional Mechanism Offers Therapeutic Advantage
Amivantamab's unique trifunctional mechanism distinguishes it from conventional anti-EGFR therapies. According to Dirk Arnold, MD, PhD, medical director at Asklepios Tumour Biology Centre, the antibody functions as both an anti-EGFR inhibitor and MET inhibitor, while also demonstrating immune cell-directed activity through its fragment crystallizable region, including antibody-dependent cytotoxicity.
"This makes this a highly interestingly attractive target for treatment of colorectal cancer," Arnold explained, noting the drug's established activity in lung adenocarcinoma.
Phase 3 Program Targets Large Patient Population
The clinical development program has expanded with two phase 3 studies targeting patients with metastatic colorectal cancer and RAS and BRAF wild-type status. The OrigAMI-2 trial (NCT06662786) will compare amivantamab versus cetuximab, both with or without chemotherapy, as first-line therapy. A second phase 3 study, OrigAMI-3 (NCT06750094), has also been initiated.
This patient population represents approximately 50% of all metastatic colorectal cancer cases, according to Arnold, who emphasized the need for improved treatment strategies in this substantial patient group.
Genomic Diversity and Resistance Patterns
Filippo Pietrantonio, MD, head of the Gastrointestinal Oncology Unit at Fondazione IRCCS Istituto Nazionale dei Tumori, noted that patients in the OrigAMI-1 trial harbored various genomic alterations typically associated with resistance to EGFR inhibition. These included mutations in TP53, APC, MAP2K1, ATM, ARID1A, PIK3CA, RB1, PTEN, KRAS, FBXW7, EGFR, CDKN2A, and BRAF.
Future Research Directions
Pietrantonio highlighted opportunities for expanding amivantamab evaluation beyond gastrointestinal cancers to other tumor types with potential sensitivity to EGFR inhibition. He emphasized the need for continued biomarker investigation and research to identify methods for overcoming resistance to first-generation inhibitors in colorectal cancer.
"There is a lot of space to also investigate biomarkers," Pietrantonio stated, pointing to the potential for broader therapeutic applications of this trifunctional antibody approach.
