BEACON CRC: a randomized, 3-Arm, phase 3 study of encorafenib and cetuximab with or without binimetinib vs. choice of either irinotecan or FOLFIRI plus cetuximab in BRAF V600E–mutant metastatic colorectal cancer

BRAF V600E mutations are identified in up to 15% of metastatic colorectal cancer (mCRC) patients and confer a poor prognosis. In patients who are refractory to initial therapy, objective response rates (ORR) to standard chemotherapy and biologic combinations are generally less than 10%, with median progression-free survival (PFS) and overall survival (OS) approximately 2 and 4-6 months, respectively. A 30-patient safety lead-in (SLI) of the BEACON CRC study assessed the safety, tolerability, and efficacy of the combination of encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) in patients with BRAF V600E-mutant mCRC after failure of 1 or 2 prior regimens, confirming the acceptable safety and encouraging activity of the triplet combination for the randomized portion of the study.

The BEACON CRC Study (NCT02928224) was a multicenter, randomized, open-label, 3-arm, phase 3 study to evaluate ENCO+CETUX with/without BINI (triplet or doublet combination) vs. investigator’s choice of irinotecan (IRI) or FOLFIRI + CETUX (control) in patients with BRAF V600E‒mutant mCRC whose disease has progressed after 1 or 2 prior regimens in the metastatic setting. The primary endpoints were OS and ORR (by blinded central review) comparing the triplet to the control arm; secondary end points included overall survival for the doublet arm compared to the control arm as well as progression-free survival, duration of response, and safety.

665 were randomly assigned to receive either the triplet combination (n = 224), doublet combination (n = 220), or one of the control regimens (n = 221). Median OS was 9.0 months (95% confidence interval [CI], 8.0-11.4) for the triplet combination and 5.4 months (95% CI, 4.8-6.6) for the control regimens (hazard ratio, 0.52; 95% CI, 0.39-0.70, P < .0001). Confirmed ORR by blinded central review of the triplet combination was 26% (95% CI, 18% to 35%) and 2% (95% CI, <1% to 7%) for control (P < .0001). Median OS for the doublet combination was 8.4 months (95% CI, 7.5-11.0) (hazard ratio vs. control, 0.60; 95% CI, 0.45-0.79; P = .0003). Adverse events were as anticipated based on prior trials with each combination. Grade 3 or higher adverse events were seen in 58% of patients in the triplet arm, 50% of patients in the doublet arm, and 61% of patients in the control arm.

In the BEACON CRC study, the combination of ENCO+BINI+CETUX improved OS and ORR in patients with BRAF V600E-mutant mCRC when compared with current standard of care chemotherapy and had a safety profile consistent with the known safety profile of each agent. This targeted therapy regimen should be a new standard of care for this patient population.