OrigAMI-3 Trial: A Novel Approach for Metastatic Colorectal Cancer

J. Randolph (Randy) Hecht, MD, professor, clinical medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), director, UCLA Gastrointestinal Oncology Program, discusses the ongoing, global, randomized, phase 3 OrigAMI-3 trial (NCT06750094) for patients with recurrent, unresectable, or metastatic RAS/BRAF wild-type colorectal cancer.

This second-line study aims to improve outcomes for a patient population that currently has limited curative options outside of surgical resection or the 3% with microsatellite instability-high disease responsive to immunotherapy.

OrigAMI-3, involving 700 patients across more than 20 countries, compares amivantamab (Rybrevant) plus FOLFIRI to standard regimens of either cetuximab or bevacizumab plus FOLFIRI, which consists of the drugs leucovorin (folinic acid), fluorouracil, and irinotecan. Amivantamab is a bispecific antibody targeting both EGFR and MET pathways. Resistance to anti-EGFR therapies, a cornerstone of colorectal cancer treatment for over two decades, often involves alternative growth factor pathways like MET. Amivantamab's dual targeting aims to overcome this resistance, building on promising results from the earlier OrigAMI-1 trial which showed significant responses and durable benefits.

“OrigAMI-3 is a second-line trial in patients who are what we call triple wild-type, meaning that they do not have a RAS or BRAF mutation or HER2 alteration. Anti-EGFR antibodies have been used in colorectal cancer for more than 20 years. I helped develop one called panitumumab [Vectibix]. They clearly have activity,” says Hecht.

Previous trials like OrigAMI-1 (NCT05379595) in a similar patient population demonstrated response rates under 30% and progression-free survival in the single-digit months, highlighting the urgent need for more effective treatments. While OrigAMI-2 (NCT06662786) is exploring amivantamab in the first-line setting for left-sided colorectal cancer, OrigAMI-3 focuses on the second-line, subcutaneous administration of amivantamab given its improved tolerability.

Hecht expresses optimism that this trial will "move the needle" for patients with metastatic colorectal cancer, particularly those who have not received anti-EGFR therapy in the first line.