Approximately 10% to 15% of patients with metastatic colorectal cancer (mCRC) carry BRAF V600E mutations, which are associated with a poor prognosis and limited treatment options. Treatment with BRAF inhibitors has historically been ineffective due to multiple feedback mechanisms present in the MAP kinase pathway, leading to resistance. In other tumor types, combination of BRAF inhibitors with MEK inhibitors has resulted in superior responses and longer survival compared to BRAF inhibitors alone. Combination with an EGFR inhibitor is another rational approach to overcome BRAF resistance. The randomized phase III BEACON CRC trial evaluated the efficacy of combined BRAF/EGFR/MEK inhibition and BRAF/EGFR inhibition in 615 patients with mCRC with BRAF V600E mutations who had progressed on 1 or 2 prior lines of therapy. In this trial, patients received either the BRAF inhibitor encorafenib plus the EGFR cetuximab (doublet), encorafenib and cetuximab plus the MEK inhibitor binimetinib (triplet), or cetuximab in combination with either irinotecan or FOLFIRI chemotherapy (control). Results of this trial were recently presented at the annual gastrointestinal (GI) congress in Barcelona by Scott Kopetz, MD (University of Texas MD Anderson Cancer Center, Houston, Texas, United States).
With a median follow-up of 7.8 months, the triplet combination of encorafenib/cetuximab/binimetinib resulted in a clinically meaningful and statistically significant improvement in overall survival (OS) compared to cetuximab plus chemotherapy (9.0 months vs 5.4 months; HR 0.52, P < .0001), the primary endpoint of the study. The OS benefit of triplet therapy was consistent across all prespecified patient subgroups examined. For patients receiving doublet therapy, median OS was superior to cetuximab plus chemotherapy (8.4 months vs 5.4 months; HR 0.60, P = .0003). The study was not powered to compare the triplet arm to the doublet arm, though there appeared to be a slight benefit for triplet therapy (9.0 months vs 8.4 months; HR 0.79). The objective response rate (ORR) was 26% in the triplet arm, 20% in the doublet arm, and 2% in the control arm. Patients who had received only 1 prior line of therapy were more likely to respond to triplet therapy. The median progression-free survival (PFS) was 4.3 months among patients receiving triplet therapy, compared to 1.5 months among patients receiving cetuximab plus chemotherapy (HR 0.38, P < .0001). A similar PFS benefit was seen with doublet therapy compared to the control (4.2 months vs 1.5 months; HR 0.40, P < .0001).
Both triplet and doublet therapy were associated with manageable adverse event (AE) profiles consistent with the known safety of these agents. There were no increases in grade 3/4 AEs between the triplet arm, the doublet arm, and the control arm (58% vs 50% vs 61%), and fewer patients discontinued due to AEs in both the triplet arm and the doublet arm compared to the control arm.
Dr Kopetz concluded that these data support the efficacy and safety of both the encorafenib/binimetinib/cetuximab triplet and the encorafenib/cetuximab doublet as treatment options for patients with mCRC with BRAF V600E mutations. Given the historically poor outcomes for this patient group and limited treatment options, Dr Kopetz indicated that that this regimen should be considered a new standard of care in appropriate, biomarker-identified patients. For more information regarding this and other mCRC studies presented during the Barcelona GI congress, please visit prIME Conference Insights in Colorectal Cancer.
Ann Oncol. 2019;30(Suppl 4): Abstract LBA-006.