Cetuximab β/FOLFIRI Prolongs Survival vs FOLFIRI in RAS/BRAF Wild-Type mCRC

The objective response rate per blinded-independent review committee assessment was 69.1% among those treated with cetuximab β vs 42.3% in those who received FOLFIRI alone.

The addition of cetuximab β (CMAB009) to irinotecan, fluorouracil, and leucovorin (folinic acid; FOLFIRI) prolonged survival outcomes compared with FOLFIRI alone while maintaining a manageable safety profile in patients with RAS/BRAF wild-type metastatic colorectal cancer (CRC), according to findings from a parallel-group phase 3 trial (NCT03206151) published in Signal Transduction and Targeted Therapy.

Data from the trial revealed that the blinded-independent review committee (BIRC)-assessed median progression-free survival between the combination and FOLFIRI-only groups was 13.1 months (95% CI, 11.2-14.0) vs 9.6 months (95% CI, 7.9-11.3; HR, 0.639; 95% CI, 0.468-0.872; P = .004). Additionally, the investigator-assessed median PFS was 11.1 months (95% CI, 9.4-11.4) vs 7.5 months (95% CI, 7.5-9.3), in respective arms (HR, 0.559; 95% CI, 0.439-0.710; P <.001).

Additionally, the median overall survival (OS) in the combination and comparator arms was 28.3 months (95% CI, 24.0-38.1) vs 23.1 months (95% CI, 19.6-24.5), respectively (HR, 0.729; 95% CI, 0.551-0.965; P = .024). Furthermore, the objective response rate (ORR) per BIRC assessment was 69.1% (95% CI, 63.2%-75.0%) vs 42.3% (95% CI, 35.9%-48.7%) in respective arms (OR, 3.090; 95% CI, 2.280-4.189; P <.001). Investigator-assessed ORRs in respective arms were 63.1% (95% CI, 56.7%-69.4%) vs 37.2% (95% CI, 30.9%-43.5%; OR, 2.890; 95% CI, 1.953-4.276).

“This study demonstrated that cetuximab β plus FOLFIRI provided significant clinical benefits as a first-line treatment for patients with RAS/BRAF wild-type [metastatic] CRC,” principal investigator Yuankai Shi, MD, PhD, of the Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs at the National Clinical Research Center for Cancer of the Chinese Academy of Medical Sciences, wrote in the publication with study coinvestigators. “Compared with FOLFIRI alone, cetuximab β plus FOLFIRI therapy led to prolonged median PFS and OS while maintaining a manageable safety profile, offering a new treatment option for the patient population.”

The open-label, multicenter phase 3 trial enrolled Chinese patients with histologically confirmed RAS/BRAF wild-type metastatic CRC and randomly assigned them 1:1 to receive either cetuximab β with FOLFIRI (n = 260) or FOLFIRI alone (n = 260). Random assignment was balanced based on ECOG performance status score and hospital location. Additionally, mutation screening was conducted using an amplification refractory mutation system with fluorescent polymerase chain reaction technology.

Patients in both arms received 180 mg/m2 of intravenous irinotecan, followed by 400 mg/m2 of intravenous leucovorin and a 400 mg/m2 bolus dose of 5-fluorouracil on day 1 of 14-day cycles. Following each FOLFIRI dose, a continuous 2400 mg/m2 5-fluorouracil infusion was given for 46 to 48 hours. Patients in the combination arm received an initial loading dose of 400 mg/m2 cetuximab β, followed by weekly maintenance doses of 250 mg/m2 on days 1 and 8 of 2-week cycles.

In the combination and chemotherapy-only arms, 69.6% vs 68.5% were male, the median age was 57 years (range, 23-74) vs 58 years (range, 23-75), and 66.9% vs 67.3% had an ECOG performance score of 1. Among respective arms, 33.1% vs 28.6% had 1 metastatic disease site, 37.0% vs 33.5% had 2, 17.9% vs 21.8% had 3, and 12.1% vs 16.1% had more than 3. The most common metastatic sites included the liver (69.6% vs 76.2%), the intraperitoneal lymph nodes (36.6% vs 41.1%), the lungs (32.3% vs 38.3%), and the extraperitoneal lymph nodes (26.5% vs 28.6%).

Most patients in both arms had a left-sided primary tumor location (85.6% vs 85.9%). Additionally, the most common previous therapies included surgery (47.9% vs 48.4%) and adjuvant chemotherapy (24.1% vs 15.7%). Furthermore, 55.6% vs 56.5% of respective arms did not undergo a primary tumor resection.

The primary end point of the study was BIRC-assessed PFS. Secondary end points included OS, ORR, disease control rate, surgery rate for metastases, the R0 resection rate, and safety.

Among those in the investigational and FOLFIRI-only arms, at least 1 grade 3 or higher treatment-emergent adverse effect (TEAE) occurred in 83.3% vs 66.9%. Additionally, the grade 3 or higher treatment-related AE (TRAE) incidence in respective arms was 78.6% vs 57.3%. The most common grade 3 or higher TRAEs included neutrophil count decreased (56.8% vs 34.7%), white blood cell decreased (32.7% vs 16.5%), diarrhea (10.1% vs 12.5%), and skin reactions including dermatitis (45.5% vs 2.4%), dermatitis acneiform (21.0% vs 0%), and palmoplantar pustulosis (11.7% vs 1.6%).

Reference

Shi Y, Ba Y, Wang J, et al. First-line treatment of anti-EGFR monoclonal antibody cetuximab β plus FOLFIRI versus FOLFIRI alone in Chinese patients with RAS/BRAF wild-type metastatic colorectal cancer: a randomized, phase 3 trial. Sig Transduct Target Ther. 2025;10:147. doi:10.1038/s41392-025-02229-4