Combining the BRAF inhibitor encorafenib with the MEK inhibitor binimetinib may significantly improve progression-free survival in BRAF mutant melanoma, according to a new phase III trial.
Combining the BRAF inhibitor encorafenib with the MEK inhibitor binimetinib may significantly improve progression-free survival (PFS) in BRAF mutant melanoma, according to a new phase III trial.
The latest results from Part 1 of the 3 COLUMBUS (Combined LGX818 Used with MEK162 in BRAF Mutant Unresectable Skin Cancer) study evaluating LGX818 (encorafenib) and MEK162 (binimetinib) in patients with BRAF-mutant advanced, unresectable or metastatic melanoma demonstrated superiority. The study met its primary endpoint, significantly improving PFS compared with vemurafenib (Zelboraf) alone.
The median PFS for patients treated with the combination of encorafenib plus binimetinib was 14.9 months versus 7.3 months for patients treated with vemurafenib (hazard ratio [HR], 0.54). The combination was generally well-tolerated and reported adverse events were overall consistent with previous combination encorafenib plus binimetinib clinical trial results in BRAF-mutant melanoma patients.
"The preliminary results from Part 1 of COLUMBUS suggest that the combination of encorafenib plus binimetinib represents a potentially unique therapy for the BRAF-mutant melanoma population," said Keith T. Flaherty, MD, who is the Director of the Termeer Center for Targeted Therapy at Massachusetts General Hospital and Professor of Medicine at Harvard Medical School, in a news release. "In addition to the robust activity observed in Part 1, the combination appeared to be generally well-tolerated."
An analysis of secondary endpoints comparing the PFS of patients treated with combination to patients treated with encorafenib showed a median of 14.9 months versus 9.6 months (HR, 0.75), which did not reach statistical significance. A complete analysis of these results will be provided to global regulatory authorities as part of planned submissions. In addition, data from Part 2 of the COLUMBUS trial are anticipated in approximately 8 months.
The COLUMBUS trial (NCT01909453) is a two-part, international, randomized, open-label phase III study evaluating the efficacy and safety of the combination of encorafenib plus binimetinib to vemurafenib and encorafenib monotherapy. The trial includes 921 patients with locally advanced, unresectable or metastatic melanoma with BRAF V600 mutation. Patients were allowed in the study if they had undergone prior immunotherapy treatment.
In Part 1, 577 patients were randomized 1:1:1 to receive the combination of 450 mg encorafenib plus 45 mg binimetinib, 300mg encorafenib alone, or 960mg vemurafenib alone. The primary endpoint for the COLUMBUS trial was a PFS comparison of the combination versus vemurafenib. Secondary endpoints included a comparison of the PFS of encorafenib monotherapy to that of the combination and a comparison of overall survival for the combination to that of vemurafenib alone.
It is now believed that approximately 50% of patients with metastatic melanoma have activating BRAF mutations, making this type of gene mutation the most common in this patient population. Binimetinib and encorafenib are investigational medicines and are not currently approved in any country.