Colorectal cancer is the third most common cancer globally, representing about 10 percent of all cancer cases. EGFR inhibitors in combination with chemotherapy are associated with an ORR of 32% to 36% in 2L RAS/BRAF WT mCRC. MET alterations are associated with metastatic progression and poor prognosis in patients with CRC and are a common mechanism of resistance to EGFR inhibitors.

Johnson & Johnson’s RYBREVANT (amivantamab) is an EGFR-MET bispecific antibody cell-directing activity that showed promising monotherapy antitumor activity in right and left-sided relapsed/refractory mCRC. Standard therapy for RAS/RAF wild-type (WT) mCRC is 5-FU–based doublet or triplet chemotherapy (FOLFOX or FOLFIRI) with or without biologics. With amivantamab unique mechanism of action, the drug has the potential to offer improved efficacy when combined with FOLFOX or FOLFIRI.

Data from a Phase I/II OrigAMI-1 study of amivantamab + FOLFOX or FOLFIRI in anti-EGFR-naïve RAS/RAF wild-type mCRC were presented in the Mini Oral Session during the ESMO 2024. Forty-three patients were treated with amivantamab along with either FOLFOX (20 patients) or FOLFIRI (23 patients). The median follow-up period was 7.3 months. The table below shows the efficacy obtained.

Among patients with measurable liver lesions, the intrahepatic ORR and DCR were 53% and 93%, respectively. Notably, nine patients were able to proceed to curative intent surgery due to strong antitumour activity.

The safety profile of amivantamab plus FOLFOX/FOLFIRI was manageable and consistent with each of the individual components, without any additive toxicity. No new safety signals were observed. The most frequent TEAEs were neutropenia, rash, stomatitis, infusion-related reactions, and diarrhea. All IRRs were Grade 1 or 2 and there were no Grade 3 or higher IRR events reported. Treatment-related discontinuations were 10% for amivantamab plus FOLFOX and 9% for amivantamab plus FOLFIRI.

KOL insights

"These data are promising and provide a strong foundation for further research. It is also encouraging that there were no unexpected or unmanageable side effects with these drug combinations. Additionally, the reduced treatment administration time of the subcutaneous formulation that will be explored in OrigAMI-2 and OrigAMI-3 offers the potential to improve patient quality of life and reduce the burden on healthcare resources." – MD, Veneto Institute of Oncology, Italy.

Conclusion 

Despite the advent of individualized treatment based on prognostic and predictive molecular markers, mCRC remains a disease with poor prognosis, with a 5-year survival rate of 14% and there is an urgent need for novel treatment options for patients who progress on standard therapies.  

The latest results from the OrigAMI-1 study presented at the ESMO 2024 demonstrate the potential of amivantamab-based combination regimen, with its multi-targeted mechanism of action to address an important unmet need in metastatic colorectal cancer. Amivantamab + FOLFOX or FOLFIRI provided promising antitumor activity in patients with EGFR inhibitor in naïve first-line or second-line RAS/BRAF WT mCRC with an ORR of 49%. OrigAMI-1 is the first study to show amivantamab plus chemotherapy may provide clinically meaningful benefits to this patient segment. 

The confirmation that amivantamab shows activity beyond lung cancer marks a potentially significant advancement for patients with EGFR inhibitor-naïve metastatic colorectal cancer. Pivotal Phase III registration trials evaluating amivantamab-based regimens as first- and second-line treatment in colorectal cancer are planned.

For more insight into the patient's burden/epidemiology, treatment, and changing market landscape-related advancements, refer to the following reports: 

• Colorectal Cancer - Market Insight, Epidemiology and Market Forecast - 2032

• Metastatic Colorectal Cancer Market Insight, Epidemiology and Market Forecast – 2032