Data from the phase 2 FIRE-4.5 trial suggest that cetuximab further reinforces a bevacizumab-based chemotherapy regimen as the frontline treatment of choice for BRAF-mutant, metastatic colorectal cancer.
Treatment with cetuximab (Erbitux) in combination with fluorouracil, folinic acid, oxaliplatin, and irinotecan (FOLFOXIRI) achieved a lower response rate than bevacizumab (Avastin) and FOLFOXIRI among patients with previously untreated, BRAF V600E–mutant metastatic colorectal cancer (CRC), according to findings from the phase 2 FIRE-4.5 study (NCT04034459) published in the Journal of Clinical Oncology.
Among patients treated according to protocol, the overall response rate (ORR) in the cetuximab arm was 50.8%—which was notably lower than the expected rate of 82.5% or higher—compared with 66.7% with the bevacizumab-based regimen—exceeding the prespecified value of 60%. The trial, thereby, did not meet its primary end point of superiority with cetuximab (odds ratio [OR], 1.93; 80% CI, 1.06-3.52; P = .92). This non-superiority remained constant after adjustment for sex, age, and ECOG performance status (OR, 2.02; 80% CI, 1.08-3.77).
The disease control rate (DCR) in the cetuximab arm was 83.1% compared with 90% in the bevacizumab arm. Median overall survival (OS) was 12.9 months vs 17.1 months with cetuximab vs bevacizumab, respectively; however, this effect was not statistically significant at an overall event rate of 64.5% (HR, 1.40; 95% CI, 0.83-2.37; P = .20). Investigators also reported that the superiority of bevacizumab was more pronounced in patients older than 65 years of age and those with liver metastasis, according to univariate testing.
Cetuximab was also inferior to bevacizumab among patients included in the full analysis set (OR, 1.87; P = .93). Median progression-free survival (PFS) in this population was 6.7 months with cetuximab vs 10.7 months with bevacizumab (HR, 1.89; 95% CI, 1.19-3.01; P = .006).
“To the best of our knowledge, FIRE-4.5 is the first randomized, prospective study investigating first-line treatment of BRAF V600E–mutant metastatic CRC,” the investigators wrote. “With regard to results obtained in BRAF-mutant cohorts treated with bevacizumab, it needs to be pointed out that FOLFOXIRI [and] bevacizumab as applied in 35 patients of [the] FIRE-4.5 [study] induced the longest median PFS…reported so far.”
The open-label FIRE-4.5 study included 109 patients who enrolled between November 2016 and December 2020, of whom 107 were included in the full analysis set and 89 were treated according to protocol. All enrolled patients were randomly assigned to either the cetuximab (n = 73) or bevacizumab (n = 36) arm. The median duration of treatment was 17.4 weeks and 22 weeks in each respective arm.
The median patient age ranged from 62 to 64 years old across all subgroups, and a minority of patients in all groups were older than 65 years. Most had an ECOG performance status of 0 and right-sided disease, except in the according-to-protocol population that received the cetuximab regimen, in which 52.5% of patients had left-sided disease.
The control regimen was administered once every 14 days and consisted of bevacizumab at a dose of 5 mg/kg, irinotecan at 150 mg/m2, oxaliplatin at 85 mg/m2, folinic acid at 400 mg/m2, and fluorouracil at 3000 mg/m2 within 48 hours. The experimental regimen was the same except with cetuximab instead of bevacizumab. Cetuximab was administered at a starting dose of 400 mg/m2 followed by 250 mg/m2 once per week. Both arms received a maximum of 12 cycles.
The primary end point of the trial was ORR per RECIST v1.1 critiera. Secondary end points included DCR, safety, PFS, and the secondary resection rate.
Skin disorders of any grade affected 66.7% of patients in the cetuximab arm, and skin disorders of grade 3 or higher affected 18.1%. Thromboembolic events of grade 3 or higher affected 5.6% vs 5.7% of patients in the cetuximab and bevacizumab arms, and neutropenia affected 26.4% vs 34.3%, respectively. Four deaths due to adverse effects (AEs) occurred in the cetuximab arm, 3 of which were tumor-related and 1 of which was treatment-related.
Among the limitations noted by investigators, patients in this study were neither excluded nor stratified based on microsatellite instability or DNA mismatch repair status. These data are also subject to potential confounding factors such as post-study treatment, and the small size of the trial may have produced relevant imbalances in baseline critieria.
“FOLFOXIRI plus bevacizumab led to a significantly longer PFS, higher ORR, and longer OS when compared with the cetuximab arm,” the investigators concluded. “Bevacizumab-based chemotherapy, doublet or triplet according to treatment goal and patient tolerability, therefore remains the preferable first-line treatment of patients with BRAF V600E-mutant metastatic CRC.”
Stintzing S, Heinrich K, Tougeron D, et al. FOLFOXIRI Plus cetuximab or bevacizumab as first-line treatment of BRAFV600E-mutant metastatic colorectal cancer: the randomized phase II FIRE-4.5 (AIO KRK0116) study. J Clin Oncol. Published online June 23, 2023. doi:10.1200/JCO.22.01420