Safety of Encorafenib Plus Binimetinib and Pembrolizumab for Advanced BRAF V600-Mutant Melanoma

Safety Lead-In Phase for the STARBOARD Trial

According to the safety lead-in phase of the phase 3 STARBOARD trial, the safety of encorafenib plus binimetinib and pembrolizumab was found to be generally consistent with the known safety profile of each agent, across both cohorts of patients with untreated, unresectable advanced BRAF V600-mutant melanoma.

STARBOARD is a randomized, double-blind, placebo-controlled, phase 3 study evaluating the efficacy, safety, and tolerability of encorafenib and binimetinib plus pembrolizumab, compared with placebo plus pembrolizumab among patients with metastatic or unresectable locally advanced BRAF V600-mutant melanoma. The initial safety lead-in for STARBOARD included patients with untreated, unresectable locally advanced or metastatic BRAF V600E/K-mutant cutaneous melanoma. Patients received 45 mg binimetinib twice daily plus 200 mg pembrolizumab every 3 weeks, with encorafenib at either 450 mg once daily (n = 20) or 300 mg once daily (n = 17). The primary end point of this study was incidence of dose-limited toxicities, with secondary end points including safety, objective response, time to response, and duration of response. A post hoc assessment evaluated progression-free survival (PFS).

The median follow-up duration within the safety lead-in phase was 19.4 months. Of the 17 patients evaluable for dose-limited toxicities in the 450 mg encorafenib cohort, 1 experienced a dose-limiting toxicity (grade 3 drug-induced liver injury with concurrent grade 4 alanine aminotransferase increase and grade 3 increased bilirubin). Of the 17 patients evaluable for dose-limited toxicities in the 300 mg encorafenib cohort, 2 experienced a dose-limited toxicity (grade 3 rheumatoid arthritis flare, n = 1; unable to receive drug do to multiple grade 3/4 events, n = 1). Grade 3/4 treatment-related adverse events were reported in 50% of patients in the 450 mg encorafenib cohort and 41.2% of patients in the 300 mg encorafenib cohort. There were no treatment-related deaths in either cohort.

In the 450 mg cohort the overall response rate was 65.0%, compared to 47.1% in the 300 mg encorafenib cohort. The median time to response was 9.1 weeks and 9.2 weeks, respectively; and the median duration of response was 15.2 weeks and not evaluable, respectively. Median PFS was 17.0 months in the 450 mg encorafenib cohort and was not evaluable in the 300 mg encorafenib cohort. The probability of being event free at 12 months was 60% and 57.3%, respectively.

Study authors concluded these results demonstrated that safety in both dosage cohorts “was generally comparable and in line with the known safety profile of each agent. In addition, the number of treatment discontinuations and reductions was similar between cohorts.” While the data was not report, authors went on to note that “encorafenib and binimetinib exposures were relatively similar to those observed in other melanoma studies.”

From these results, the recommended phase 3 dose for the STARBOARD trial is 450 mg encorafenib once daily, with 45 mg binimetinib twice daily and 200 mg pembrolizumab every 3 weeks with.

Source:

Dudnichenko O, Penkov K, McKean M, et al. First-line encorafenib plus binimetinib and pembrolizumab for advanced BRAF v600-mutant melanoma: Safety lead-in results from the randomized phase III STARBOARD study. European Journal of Cancer. Published online: October 10, 2024. doi: 10.1016/j.ejca.115070.