Amivantamab: Overcoming Resistance in RAS/BRAF Metastatic CRC

In an interview with Targeted Oncology, Filippo Pietrantonio, MD, Fondazione IRCCS Istituto Nazionale dei Tumori, discusses the clinical necessity of overcoming resistance to first-generation EGFR inhibitors in patients with RAS/BRAF wild-type, relapsed/refractory metastatic colorectal cancer. This unmet need prompted the ongoing OrigAMI series of clinical trials (OrigAMI-1, NCT05379595; OrigAMI-2, NCT06662786; OrigAMI-3, NCT06750094) evaluating amivantamab (Rybrevant) plus FOLFOX/FOLFIRI chemotherapy in this population.

Read the full interview here.

For patients with RAS/BRAF wild-type metastatic colorectal cancer, particularly those with left-sided tumors, the current standard of care consists of doublet chemotherapy paired with first-generation EGFR inhibitors such as cetuximab (Erbitux) or panitumumab (Vectibix). While this combination is the guideline-recommended and preferred option for initial therapy, clinicians frequently encounter primary endocrine resistance to EGFR inhibition in practice. This clinical challenge has created a significant unmet need for novel agents that can improve patient outcomes beyond what is achievable with current standard regimens.

Amivantamab is being investigated as a solution to these efficacy gaps due to its unique, multifaceted mechanism of action. As a bispecific antibody, it targets both EGFR and MET receptors, which is critical as MET inhibition can address the functional bypass signaling and crosstalk that occurs when EGFR is blocked. Unlike first-generation inhibitors, amivantamab induces greater receptor internalization and degradation. Additionally, it utilizes an immunological mechanism of action, which includes immune cell-directing activity to further combat tumor growth.