Amivantamab Plus Chemotherapy Delivers Durable Responses in RAS/BRAF Wild-Type mCRC: Filippo Pietrantonio, MD
Filippo Pietrantonio, MD, discusses findings from the phase 1/2 OrigAMI-1 study in RAS/BRAF wild-type mCRC.
At this year’s
With durable responses, encouraging survival outcomes, and evidence that some patients may become eligible for curative-intent surgery, the combination of amivantamab with standard chemotherapy could signal a meaningful shift in how this molecularly defined population is treated.
This transcript was lightly edited for clarity.
The American Journal of Managed Care® (AJMC®): Can you provide a brief background of the study?
Pietrantonio: OrigAMI-1 is a phase 1/2 study investigating the role of the bispecific EGFR-MET [mesenchymal-epithelial transition] monoclonal antibody amivantamab in patients with wild-type colorectal cancer. This study was a proof-of-concept, signal-seeking trial investigating amivantamab, a next-generation EGFR inhibitor with a trimodal mechanism of action. The agent works through EGFR receptor blockade, receptor internalization and degradation, and cell-directing activity.
The study was a multicohort study, including 3 monotherapy cohorts: left-sided EGFR-refractory patients, left-sided EGFR-experienced patients, and right-sided patients previously exposed to EGFR inhibitors.
In this poster at ASCO GI 2026, data from the 2 chemotherapy combination cohorts were presented. In these cohorts, patients with no more than 1 prior line of therapy and who were EGFR-naive were treated with either FOLFIRI [leucovorin (folinic acid), fluorouracil, and irinotecan] plus amivantamab or FOLFOX [folinic acid, fluorouracil, and oxaliplatin] plus amivantamab. Updated results were presented here.
AJMC: With an overall response rate (ORR) of 51% and some patients on treatment for more than 1 year, how do you interpret the clinical impact of these longer follow-up results for amivantamab plus chemotherapy?
Pietrantonio: This is really promising, because I remember when I presented the initial results of these 2 chemotherapy combination cohorts, which was at ESMO [European Society for Medical Oncology] 2023, with updated results and a median follow-up of 16 months, the outcomes had improved compared with the presentation 2 years ago. Basically, the response rate is slightly improved with additional follow-up, and a 51% overall response rate in patients treated mostly in the second-line setting is really promising considering historical data with first-generation EGFR inhibitors in combination with doublet chemotherapy.
These results compare favorably because progression-free survival of 9.2 months is definitely worth further investigation. This is also the reason why there are 3 ongoing studies to confirm these positive results, because OrigAMI-1 is, of course, a nonrandomized clinical trial, so randomized, prospective confirmation is needed.
AJMC: Responses were higher in the first-line subgroup. How might this influence where amivantamab fits in the mCRC treatment sequence?
Pietrantonio: Absolutely. The results were, of course, translated in the first-line set, representing a small cohort, so we cannot draw negative conclusions, but the results in terms of response rate and progression-free survival were definitely in the first line. This is expected because, of course, these patients are both chemotherapy and EGFR naive, and using amivantamab with the bispecific mechanism of action related to both EGFR and MET may further increase the efficacy of the treatment.
In general, the future role of amivantamab, and the aim, will be to replace the current agent, the used and recommended EGFR inhibitors in the first-line setting, cetuximab or panitumumab. Of course, according to the current guidance, first-line treatment in patients with left-sided RAS/BRAF wild-type tumors is usually represented by the combination of doublet chemotherapy plus a first-generation EGFR inhibitor. But, of course, the future role of amivantamab may be really to replace first-gen EGFR inhibitors and potentially find the use of EGFR inhibition in the first setting for other difficult-to-treat populations, including [those] with right-sided tumors or patients whose usual related alterations usually relate to primary resistance to first-generation EGFR inhibitors.
AJMC: Several patients were able to undergo curative-intent surgery. What factors contributed to this, and how should it guide future studies?
Pietrantonio: Yeah, so this is a very interesting point, because 6 patients in these cohorts were able to achieve a secondary resection of metastasis. And please remember that the patients enrolled in this study had initially resectable metastatic disease. Also, that depth of response is important, and it may be speculated that HGF [hepatocyte growth factor] may drive the liver and tumor microenvironment and lead to higher efficacy of amivantamab thanks to the dual blockade of EGFR and MET, leading to higher responses in patients with liver metastasis.
In fact, in the outcome, in terms of tumor response and progression-free survival, it was slightly superior in patients with liver metastasis, which is a poor prognostic subgroup indeed. It is important to continue to investigate the role of amivantamab in this patient population, considering that a very large fraction of patients with metastatic colorectal cancer have or will develop liver metastatic disease.
It is important to notice that patients undergoing liver resection in the OrigAMI-1 study were censored at the time of surgery, and this is because the protocol pre-specified to follow this censoring process for these patients. But anyways, these patients achieving such high efficacy and the possibility to achieve surgical resection of metastasis didn’t contribute, actually, due to the study design, to the progression-free survival results. I can imagine that if we may consider these patients as part of the cohort of progression-free survival, it would then even bear with these patients added to the progression-free survival calculation.
In my opinion, there will also be a role in the conversion setting, in patients with unresectable liver metastasis potentially convertible to radical surgery. And this is important because it has a very deep impact on the life expectancy of patients.
AJMC: With EGFR- and MET-related toxicities, what patient characteristics or monitoring strategies are key to safely delivering amivantamab combinations?
Pietrantonio: Amivantamab safety is in line now with the expected safety of this monoclonal antibody. Nowadays, the subcutaneous administration of amivantamab is really able to reduce infusion-related reactions, although in the OrigAMI-1 study, we still used the intravenous formulation. But the next-generation and ongoing phase 3 studies are really looking at the subcutaneous use of amivantamab, further improving tolerability and patient compliance, and it is a preferable treatment administration from every point of view.
Of course, the combination of amivantamab with doublet chemotherapy, either FOLFOX or FOLFIRI, did not increase toxicity, and the safety profile was manageable. The treatment-related adverse events were clearly due to the use of amivantamab, especially skin rash, or to the use of chemotherapy, without any new safety signals. This is the reason why this combination is now being investigated in the phase 3 setting, either in the first line in the OrigAMI-2 study or in the second line in the OrigAMI-3 study in patients with RAS/BRAF wild-type colorectal cancer.
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