Binimetinib, Encorafenib, and Cetuximab Triplet Therapy for Patients With BRAF V600E-Mutant Metastatic Colorectal Cancer: Safety Lead-In Results From the Phase III BEACON Colorectal Cancer Study

Abstract

Purpose: To determine the safety and preliminary efficacy of selective combination targeted therapy for BRAF V600E-mutant metastatic colorectal cancer (mCRC) in the safety lead-in phase of the open-label, randomized, three-arm, phase III BEACON Colorectal Cancer trial ( ClinicalTrials.gov identifier: NCT02928224; European Union Clinical Trials Register identifier: EudraCT2015-005805-35).

Patients and methods: Before initiation of the randomized portion of the BEACON Colorectal Cancer trial, 30 patients with BRAF V600E-mutant mCRC who had experienced treatment failure with one or two prior regimens were to be recruited to a safety lead-in of encorafenib 300 mg daily, binimetinib 45 mg twice daily, plus standard weekly cetuximab. The primary end point was safety, including the incidence of dose-limiting toxicities. Efficacy end points included overall response rate, progression-free survival, and overall survival.

Results: Among the 30 treated patients, dose-limiting toxicities occurred in five patients and included serous retinopathy (n = 2), reversible decreased left ventricular ejection fraction (n = 1), and cetuximab-related infusion reactions (n = 2). The most common grade 3 or 4 adverse events were fatigue (13%), anemia (10%), increased creatine phosphokinase (10%), increased AST (10%), and urinary tract infections (10%). In 29 patients with BRAF V600E-mutant tumors (one patient had a non-BRAF V600E-mutant tumor and was not included in the efficacy analysis), the confirmed overall response rate was 48% (95% CI, 29.4% to 67.5%), median progression-free survival was 8.0 months (95% CI, 5.6 to 9.3 months), and median overall survival was 15.3 months (95% CI, 9.6 months to not reached), with median duration of follow-up of 18.2 months (range, 16.6 to 19.8 months).

Conclusion: In the safety lead-in, the safety and tolerability of the encorafenib, binimetinib, and cetuximab regimen is manageable and acceptable for initiation of the randomized portion of the study. The observed efficacy is promising compared with available therapies and, if confirmed in the randomized portion of the trial, could establish this regimen as a new standard of care for previously treated BRAF V600E-mutant mCRC.

FIG 1.

Patient disposition. (*) One treated patient had a non-V600 BRAF mutation (BRAF G466V). (†) Includes two patients with changes in condition or development of an intercurrent illness. (‡) Dose interruption for more than 28 consecutive days. (§) As of the data cutoff date of September 2, 2018. AE, adverse event.

FIG 2.

Best percent change from baseline in sum of tumor diameters based on (A) local assessment and (B) central assessment. One patient was without postbaseline sum of diameters (not presented). Colors represent best response (confirmed) of partial response (PR) or complete response (CR). The category other represents stable disease (SD) or not evaluable (NE). Patients with CR, defined as the disappearance of all target lesions, could have pathologic lymph node metastases present; target or nontarget lymph node metastases must have had reduction in short axis to less than 10 mm. The other category includes stable disease or patient not evaluable.

FIG 3.

Kaplan-Meier plots of (A) progression-free survival (PFS; local assessment) and (B) overall survival (OS). NR, not reached.