Triplet Combo Regimen Defines New Standard of Care for Patients With BRAF V600E-Mutant Metastatic CRC

Barcelona, Spain—Data from the BEACON CRC trial presented at the ESMO 21st World Congress on Gastrointestinal Cancer show improved survival and response rates in patients with BRAF V600E-mutant metastatic colorectal cancer (CRC) who receive a triplet targeted therapy regimen versus current standard of care chemotherapy.

“BRAF V600E mutations are identified in 10% to 15% of metastatic [CRC] patients and confer a poor prognosis,” explained Scott Kopetz, MD, PhD, FACP, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, Texas, who presented the results on behalf of his colleagues.

Studies with irinotecan-based chemotherapy have poor outcomes, and BRAF inhibitors alone are not effective due to feedback activation of EGFR in BRAF-mutant CRC, which leads to continued cell proliferation. The study team hypothesized that this feedback may be overcome by targeting multiple nodes in the pathway.

According to findings from a 30-patient safety lead-in of the BEACON CRC study, use of the combination of encorafenib (ENCO) plus binimetinib (BINI) plus cetuximab (CETUX) in patients with metastatic CRC and BRAF V600E mutation that did not respond to 1 or 2 previous regimens was safe and yielded encouraging activity in randomized portion of the study.

The 3-arm, multi-center, open-label, phase 3 BEACON CRC trial evaluating ENCO plus CETUX with or without BINI (ie, triplet and doublet arms, respectively) versus investigator’s choice of irinotecan or FOLFIRI plus CETUX (control) in patients with BRAF V600E-mutant metastatic CRC that progressed after 1 or 2 previous regimens in the metastatic setting involved 665 patients.

A total of 224 patients were randomized to receive the triplet therapy, 220 to receive the doublet therapy, and 221 to the control arm.

The primary endpoint in the initial study design was overall survival (OS) in the triplet arm vs the control arm. Based on encouraging results in the lead in to the study, the design was then amended to allow assessment of the overall response rate (ORR) in the first 330 patients who were randomized, Dr Kopetz said. Secondary study endpoints included OS for the doublet arm versus the control arm, as well as progression-free survival, duration of response, and safety.

“I’m pleased to report that the primary endpoint was met,” Dr Kopetz said. A median OS of 9.0 months (95% CI, 8.0-11.4) was demonstrated for the triplet combination versus 5.4 months (95% CI, 4.8-6.6) for the control regimens (hazard ratio [HR], 0.52; 95% CI, 0.39-0.70; P <.0001), and confirmed ORR was 26% for the triplet combination (95% CI, 18% to 35%) versus 2% for the control arm (95% CI, <1% to 7%; P <.0001).

For the doublet combination, the median OS was 8.4 months (95% CI, 7.5-11.0), showing a statistically significant improvement vs the control arm (HR, 0.60; 95% CI, 0.45-0.79; P = .0003).

“Toxicity was reasonable and consistent with our expectation of the individual component therapies,” Dr Kopetz said. Adverse events of grade ≥3 were observed in 58%, 50%, and 61% of patients in the triplet, doublet, and control arms, respectively.

“In the BEACON CRC study, the combination of ENCO+BINI+CETUX significantly improved OS and ORR relative to the current standard of care in patients with BRAF V600E-mutant metastatic CRC,” Dr Kopetz said.

“This is the first evidence of survival benefit for a chemotherapy-free targeted treatment regimen in prospective biomarker-defined patients with mCRC, defining a new standard of care,” concluded Dr Kopetz. “Furthermore, results suggest efficacy may be even greater in earlier lines of therapy.”—Hina Khaliq

Kopetz S, Grothey A, Van Cutsem E, et al. 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. Presented at: the ESMO 21st World Congress on Gastrointestinal Cancer; July 3-6, 2019; Barcelona, Spain. Abstract LBA-006.