Johnson & Johnson’s investigational amivantamab in combination with chemotherapy has demonstrated promising and durable responses in patients with metastatic colorectal cancer, according to new longer-term data from the Phase 1b/2 OrigAMI-1 study. The bispecific antibody, amivantamab-vmjw, targets both epidermal growth factor receptor (EGFR) and MET, and when paired with FOLFOX or FOLFIRI chemotherapy, showed a notable overall response rate (ORR) of 51% in patients with RAS/BRAF wild-type metastatic colorectal cancer.
These results, presented at the 2026 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, are particularly encouraging for a disease where treatment options have seen limited progress. Historically, second-line treatment for metastatic colorectal cancer with progression after first-line therapy has yielded response rates between 32-36% and median progression-free survival (PFS) of approximately 5.4 to 6.4 months. The amivantamab combination appears to significantly improve upon these outcomes.
A key highlight of the study is the sustained efficacy observed. In the first-line subgroup, over 70% of patients responded to amivantamab plus chemotherapy, with most responses lasting beyond 16 months, and some extending beyond two years. This duration of response is a critical factor in improving patient outcomes and quality of life.
Furthermore, the combination therapy showed notable activity in patients with liver metastases, a group that typically faces poorer prognoses. The ORR in this challenging subgroup was 57%, with a median PFS of 11.3 months, suggesting amivantamab’s potential to overcome common resistance mechanisms in advanced disease.
The study’s safety profile remained consistent with previous amivantamab studies and the known side effects of chemotherapy. Treatment-related discontinuations were low, with only 9% of patients discontinuing due to adverse events. The most common Grade 3 or higher event was neutropenia, and no new safety concerns were identified.
Colorectal cancer remains a significant global health challenge, ranking as the third most commonly diagnosed cancer worldwide. While traditionally affecting older populations, there’s a concerning rise in incidence among younger adults. More than half of patients eventually develop metastatic disease, with liver involvement being prevalent. The emergence of resistance to existing therapies, often driven by alterations in pathways like MET, underscores the need for novel treatment strategies that can target multiple resistance mechanisms simultaneously.
The dual-targeting approach of amivantamab, addressing both EGFR and MET, is particularly relevant given the biological understanding of resistance in colorectal cancer. Research has indicated that MET alterations frequently contribute to resistance against EGFR inhibitors, making a combined approach a logical next step in advancing treatment paradigms.
Johnson & Johnson is advancing this research with pivotal Phase 3 studies, OrigAMI-2 and OrigAMI-3, which are evaluating subcutaneous amivantamab in combination with FOLFOX and FOLFIRI for both first- and second-line colorectal cancer patients. These ongoing trials aim to further solidify the potential of amivantamab-based regimens in this difficult-to-treat cancer.
The company’s experience with amivantamab in EGFR-driven lung cancer is being leveraged to explore its efficacy in other solid tumors, including colorectal cancer, where these pathways play a crucial role. This cross-application of drug development insights highlights a strategic approach to maximizing the therapeutic potential of targeted agents.
The OrigAMI-1 study enrolled patients with RAS/BRAF wild-type metastatic colorectal cancer who were negative for KRAS, NRAS, BRAF, and EGFR mutations, and did not have HER2 amplification. Patients could have received one prior line of systemic therapy, but prior EGFR inhibitor treatment was not permitted. The study’s primary endpoint was safety, with secondary endpoints including ORR, duration of response (DOR), clinical benefit rate, and PFS. Overall survival was assessed as an exploratory endpoint.
At a median follow-up of 16 months, the amivantamab plus chemotherapy combination demonstrated a median DOR of 9.3 months and a median PFS of 9.2 months. These results indicate that the observed responses are not only frequent but also sustained, offering a meaningful benefit to patients.
The robust clinical development program for amivantamab, including its ongoing investigation in multiple solid tumors and formulations (intravenous and subcutaneous), reflects a significant commitment to addressing unmet needs in oncology. The development of subcutaneous formulations, in particular, aims to improve patient convenience and potentially broaden access to this therapy.
This research signifies a promising advancement in the landscape of colorectal cancer treatment, offering a new therapeutic avenue that targets key resistance mechanisms and demonstrates durable efficacy, particularly in patient populations with historically poor outcomes.
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