Amivantamab Combination Therapy Shows Promise in Advanced Colorectal Cancer, Potential for Curative Surgery
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A novel combination therapy featuring amivantamab is demonstrating encouraging results in the treatment of advanced or metastatic colorectal cancer (mCRC), potentially shifting treatment paradigms and even opening doors for curative-intent surgery in select patients. new data presented at the American Society of Clinical Oncology (ASCO) Gastrointestinal (GI) Cancers Symposium from the OrigAMI-1 (NCT0537959) study highlights the potential of amivantamab, a bispecific EGFR-MET monoclonal antibody, in patients with wild-type colorectal cancer.
The 1/2 study was designed to evaluate the role of amivantamab in patients with wild-type colorectal cancer. According to a lead researcher,the study served as a “proof-of-concept,signal-seeking trial” investigating amivantamab’s unique trimodal mechanism of action – blocking EGFR receptors,internalizing and degrading them,and directly targeting cells. The study included multiple cohorts, but recent data presented focused on two chemotherapy combination groups: patients receiving FOLFIRI (leucovorin, fluorouracil, and irinotecan) plus amivantamab, and those receiving FOLFOX (folinic acid, fluorouracil, and oxaliplatin) plus amivantamab. Participants in these cohorts had received no more than one prior line of therapy and were EGFR-naive.
Meaningful Response Rates and Progression-Free Survival
The updated results reveal an overall response rate (ORR) of 51%,with some patients remaining on treatment for over a year.A senior official stated that these findings are particularly promising when compared to past data with first-generation EGFR inhibitors used in combination with doublet chemotherapy. The progression-free survival of 9.2 months also warrants further inquiry, prompting the initiation of three ongoing, randomized studies to confirm these positive signals.”OrigAMI-1 is, of course, a nonrandomized clinical trial, so randomized, prospective confirmation is needed,” one analyst noted.
Potential for First-Line Treatment and Broader Submission
Responses were notably higher in the first-line subgroup, suggesting a potential shift in how amivantamab is integrated into the mCRC treatment sequence. Researchers believe amivantamab’s bispecific action targeting both EGFR and MET could enhance treatment efficacy, particularly in patients who are both chemotherapy and EGFR-naive. The ultimate goal, according to a medical oncologist, is for amivantamab to replace current first-line EGFR inhibitors like cetuximab or panitumumab. This could extend to tough-to-treat populations, including those with right-sided tumors or those exhibiting primary resistance to first-generation EGFR inhibitors.
A Path Towards Curative Surgery
Perhaps the most striking finding from the OrigAMI-1 study is that six patients were able to undergo curative-intent surgery following treatment with amivantamab-based combinations. These patients initially presented with resectable metastatic disease, and the depth of response achieved with amivantamab appeared to be a key factor. Researchers speculate that amivantamab’s dual blockade of EGFR and MET may effectively target the liver tumor microenvironment, leading to improved responses in patients with liver metastasis – a historically poor prognostic subgroup. While patients undergoing resection were censored from the progression-free survival analysis per protocol, researchers believe that including these patients in the calculation would further bolster the positive results. There is growing interest in exploring amivantamab’s role in a conversion setting, aiming to make previously unresectable liver metastases amenable to radical surgery, which could significantly improve patient life expectancy.
The safety profile of amivantamab in combination with doublet chemotherapy appears manageable, with treatment-related adverse events primarily attributed to amivantamab (such as skin rash) or the chemotherapy itself. The move towards subcutaneous governance of amivantamab, currently being investigated in phase 3 trials (OrigAMI-2 and OrigAMI-3), is expected to further improve tolerability and patient compliance. The ongoing phase 3 studies will evaluate amivantamab in both first-line and second-line settings for patients with RAS/BRAF wild-type colorectal cancer.
