New OrigAMI-1 Data Signal Shift Beyond First-Gen EGFR Inhibitors in Metastatic CRC

In the evolving landscape of metastatic colorectal cancer, managing patients with RAS/BRAF wild-type tumors remains a priority. While the current standard of care—combining doublet chemotherapy with first-generation EGFR inhibitors like cetuximab (Erbitux) or panitumumab (Vectibix)—is effective for initial therapy, many patients eventually face primary endocrine resistance.

To address this unmet need, investigators are exploring the therapeutic potential of amivantamab (Rybrevant), an EGFR/MET bispecific antibody that has shown clinical activity across numerous solid tumors and is FDA-approved for EGFR-mutated advanced non–small cell lung cancer. At the 2026 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, updated data from the phase 1b/2 OrigAMI-1 study (NCT05379595) highlighted promising clinical activity with amivantamab in combination with FOLFOX/FOLFIRI chemotherapy in this population, building on previous positive findings presented at the European Society for Medical Oncology (ESMO) Congress in 2023.¹

In an interview with Targeted Oncology, Filippo Pietrantonio, MD, medical oncologist and head of the Gastrointestinal Oncology Unit at the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy, discussed the biological rationale for dual EGFR/MET inhibition and how these latest findings are shaping ongoing phase 3 trials and future treatment strategies for this patient population.

Targeted Oncology: What are the key unmet needs in this patient population, specifically those with the RAS/BRAF wild type?

Filippo Pietrantonio, MD: We know that in this patient population, first-generation EGFR inhibitors are a standard of care, especially nowadays. In properly selected patients with RAS and BRAF and especially left-sided tumors, the combination of doublet chemotherapy with either FOLFOX or FOLFIRI plus cetuximab or panitumumab is the standard of care, and it's a guideline-recommended option. It's actually the preferred option for initial therapy of this patient population. However, patients are facing primary endocrine resistance to EGFR inhibition, and this is something that we routinely see in clinical practice. So, there is the need to improve outcomes of these regimens with novel agents.

The role of amivantamab may be to [not only] increase efficacy, but [also to] overcome several resistance mechanisms… [It increases efficacy] thanks to its peculiar mechanism of action, which includes not only receptor blockade—similar to first-generation inhibitors—but also… MET receptor blockade [and] the bispecific mechanism of action. We know that there is crosstalk between EGFR and MET, and MET inhibition is [a] functional bypass mechanism when EGFR is blocked. There is also greater receptor internalization and degradation induced by amivantamab compared with first-generation EGFR inhibitors.

Finally—this is very important—use of amivantamab is related to an immunological mechanism of action, including immune cell-directing activity. This is why ongoing phase 3 studies, OrigAMI-2 [NCT06662786] in the first-line setting and OrigAMI-3 [NCT06750094] in the second-line setting, [are] investigat[ing] amivantamab to replace the current strategies.

Could you briefly describe the design of OrigAMI-1, including its objectives and methods?

OrigAMI-1 was a phase 1b/2 study. In this multicenter trial, there were different cohorts—cohorts A, B, and C—investigating amivantamab monotherapy in patients with left-sided RAS/BRAF wild-type tumors: not pretreated with EGFR inhibitors in cohort A; same patient population in cohort B, but after previous exposure to first-generation EGFR inhibitors; and then patients with right-sided RAS/BRAF wild-type tumors in cohort C, regardless of prior exposure to EGFR inhibitors.

In this particular report at ASCO GI 2026, the updated results of the combination chemotherapy cohorts were presented. In cohorts D and E, amivantamab was combined with FOLFOX or FOLFIRI in patients after no more than 1 prior treatment line, so in patients with potentially chemo-sensitive disease. Patients were therefore treated in the first- and second- line setting with the combination of doublet chemotherapy plus amivantamab, and the results were quite promising.

What were the most important efficacy and safety findings from this latest analysis, and how do the data compare with earlier reports? What is the clinical significance of these findings?

These results support the ongoing phase 3 studies and the results compared with the previous European Society for Medical Oncology [ESMO] presentation. The overall response rate of the combination of chemo plus amivantamab was 51% and the median progression-free survival [PFS] was 9.2 months. This is particularly promising in this patient population. Most of the patients were treated in the second-line setting.

Six patients were able to undergo secondary resection of liver metastases, and this is particularly important because it's a direct consequence of the high activity of this combination observed in the study, and the possibility to achieve surgery of metastatic disease. These patients undergoing secondary surgery were censored at the time of surgery as predefined in the protocol. Therefore, despite the very good outcome after liver resection, these patients did not contribute to the PFS calculation. So, we could imagine that the results could have been even better [with] this patient population, as it is usually done when we evaluate the effect of the treatment.

Another key point was that in the first-line setting, the overall response rate exceeded 70%, so this was highly promising despite the limited number of patients. In the second-line setting, the response rate exceeded 40%. This is again promising.

Therefore, this is the key result of the study. We know that in this patient population, the safety was quite in line with the expected safety of each agent, chemotherapy and amivantamab, with no additive toxicity and no new safety signal.

This is again supporting the ongoing phase 3 studies with the combination of amivantamab and [either FOLFOX or FOLFIRI] chemotherapy. In these phase 3 trials, the subcutaneous formulation of amivantamab [Rybrevant Faspro] is [being] used, while in OrigAMI-1, intravenous amivantamab was adopted. The subcutaneous formulation in the future will provide a more convenient route of administration and a [greater] chance of better compliance for patients treated with this combination.

Regarding the few patients who underwent curative-intent surgery, do these cases suggest a broader role for amivantamab in converting some patients to surgical candidates?

Definitely, this is a possibility. Amivantamab[‘s role] in increasing conversion surgery or even allowing liver transplantation in some selected patients is related to the high response rate. We will investigate in larger studies, such as the ongoing phase 3 studies, whether the use of amivantamab plus chemo is associated with a better depth of response and early tumor shrinkage compared with first-generation EGFR inhibitors.

The quality and extent of response may be related to a higher percentage and higher chance to achieve secondary resection of metastasis. The primary focus is the liver, but other metastases may undergo surgical resection, including lung metastasis, peritoneal metastasis, and sometimes lymph nodal metastases. In patients [with colorectal cancer], the role of surgery is quite well established.

In addition, there may be—this is, of course, a speculation—space to demonstrate whether the mechanism of action of amivantamab may be associated with the higher tumor response in the liver. This may be related to the higher production of HGF, which is the ligand of the MET receptor in the liver microenvironment. So, there may be a biological rationale for the observed higher response rate in the liver compared with the overall population in the OrigAMI-1 study despite the limited sample size.

REFERENCES

1. Chen EX, Malik RA, Su HYL, et al. Amivantamab plus FOLFOX or FOLFIRI in RAS/BRAF wild-type metastatic colorectal cancer: Long-term follow-up from the phase 1b/2 OrigAMI-1 study. J Clin Oncol. 2026;44(2_suppl):166-166. doi:10.1200/jco.2026.44.2_suppl.166