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Combined BRAF-MEK inhibition for advanced BRAF-mutant melanoma led to significantly better progression-free survival (PFS) as compared with single-agent BRAF inhibition, according to a randomized trial.

Patients who received encorafenib (Braftovi) plus binimetinib (Mektovi) had a median PFS of 12.9 months as compared with 9.2 and 7.4 months for two cohorts treated with encorafenib alone. The outcome added to previously reported results that demonstrated the combination's superiority versus single-agent vemurafenib (Zelboraf) and a numerical advantage compared with single-agent encorafenib.

The combination was better tolerated and associated with a higher relative dose intensity versus encorafenib alone, reported Paolo A. Ascierto, MD, of Istituto Nazionale dei Tumori in Naples, Italy, and co-authors in the .

"Together with part 1 results, these data confirm and extend the evidence for the contribution of binimetinib for the treatment of BRAF-mutant, advanced, unresectable melanoma," the authors concluded. "These results suggest that maximizing BRAF inhibition in the [approved higher-dose combination] should be used on the basis of available evidence from ."

Consistent data from four randomized, phase III trials involving three different anti-BRAF-MEK combinations have established the "central dogma of optimizing BRAF-targeted therapy" for advanced melanoma with the addition of a MEK inhibitor, noted Ryan J. Sullivan, MD, of Massachusetts General Hospital Cancer Center in Boston, in an .

"However, past and emerging data support the use of frontline immunotherapy instead of BRAF-targeted therapy, and thus a number of efforts now are underway to optimize BRAF-targeted therapy in patients with advanced melanoma," he wrote.

"Part 2 of the COLUMBUS study has reinforced that MEK inhibition is critical for the efficacy and safety of BRAF inhibition in patients with advanced BRAF^V600-mutant melanoma," he added. "The next questions to be answered -- When should BRAF-targeted therapy be used? What effect does adjuvant therapy play on optimal timing of BRAF-targeted therapy use? Can triplet or quadruplet regimens improve upon the efficacy of combined BRAF/MEK inhibition without prohibitive toxicity? -- are numerous and more challenging."

Ascierto and co-authors reported findings from an FDA-requested study to confirm the specific contributions of binimetinib to the combination's efficacy versus single-agent encorafenib, with the MEK inhibitor in part 2 given at the same dosage in both arms (300 mg once daily). Patients assigned to the combination received encorafenib plus binimetinib (45 mg twice a day; COMBO300).

In the -- where patients had received encorafenib 450 mg once daily plus binimetinib 45 mg twice a day (COMBO450) or a 300-mg daily dose of encorafenib -- the PFS difference between the combination and single-agent encorafenib did not achieve statistical significance (P=0.051).

Part 2 was initiated by protocol amendment while part 1 was in progress. Patients with previously untreated advanced, unresectable melanoma were randomized 3:1 to COMBO300 or encorafenib 300 mg. The primary endpoint of COLUMBUS was PFS for COMBO450 versus vemurafenib. A key secondary endpoint was PFS for the comparison of COMBO300 versus all patients who received encorafenib alone during parts 1 and 2 of the trial.

Data analysis comprised 258 patients randomized to COMBO300, 194 patients randomized to single-agent encorafenib in part 1, and 86 in part 2. Median follow-up was 54.4 months for COMBO300, 43.5 months for encorafenib parts 1 and 2, and 57.1 months for encorafenib during part 2.

The results showed a median PFS of 12.9 months for COMBO300 versus 9.2 months for encorafenib parts 1 and 2. The difference represented a 26% reduction in the hazard ratio for disease progression or death (P=0.003). A separate analysis of the encorafenib arm in part 2 produced a median PFS of 7.4 months.

Median overall survival was 27.1 months with COMBO300 versus 22.7 months with encorafenib (parts 1 and 2), representing a nonsignificant 10% reduction in the hazard ratio (95% CI 0.73-1.11).

The most commonly reported grade 3/4 adverse events (AEs) with COMBO300 were increased creatine phosphokinase (7.4%), hypertension (6.6%), increased gamma-glutamyl transferase (GGT, 5.8%), increased alanine aminotransferase (5.1%), and anemia (4.3%). The most common grade 3/4 AEs with encorafenib (parts 1 and 2) were hand-foot syndrome (11.2%), arthralgia (9.1%), myalgia (8.3%), increased GGT (4.35), and vomiting (4.0%).

The proportion of patients achieving a relative dose intensity ≥80% was 87% for encorafenib and 80.6% for binimetinib in the combination arm versus 51.8% for encorafenib in both parts of the study combined.

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