COLUMBUS 5-Year Update: A Randomized, Open-Label, Phase III Trial of Encorafenib Plus Binimetinib Versus Vemurafenib or Encorafenib in Patients With BRAF V600-Mutant Melanoma

Abstract

Purpose: Combination treatment with BRAF and MEK inhibitors has demonstrated benefits on progression-free survival (PFS) and overall survival (OS) and is a standard of care for the treatment of advanced BRAF V600-mutant melanoma. Here, we report the 5-year update from the COLUMBUS trial (ClinicalTrials.gov identifier: NCT01909453).

Methods: Patients with locally advanced unresectable or metastatic BRAF V600-mutant melanoma, untreated or progressed after first-line immunotherapy, were randomly assigned 1:1:1 to encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, vemurafenib 960 mg twice daily, or encorafenib 300 mg once daily. An updated analysis was conducted 65 months after the last patient was randomly assigned.

Results: Five hundred seventy-seven patients were randomly assigned: 192 to encorafenib plus binimetinib, 191 to vemurafenib, and 194 to encorafenib. The 5-year PFS and OS rates with encorafenib plus binimetinib were 23% and 35% overall and 31% and 45% in those with normal lactate dehydrogenase levels, respectively. In comparison, the 5-year PFS and OS rates with vemurafenib were 10% and 21% overall and 12% and 28% in those with normal lactate dehydrogenase levels, respectively. The median duration of response with encorafenib plus binimetinib was 18.6 months, with disease control achieved in 92.2% of patients. In comparison, the median duration of response with vemurafenib was 12.3 months, with disease control achieved in 81.2% of patients. Long-term follow-up showed no new safety concerns, and results were consistent with the known tolerability profile of encorafenib plus binimetinib. Interactive visualization of the data presented in this article is available at COLUMBUS dashboard.

Conclusion: In this 5-year update of part 1 of the COLUMBUS trial, encorafenib plus binimetinib treatment demonstrated continued long-term benefits and a consistent safety profile in patients with BRAF V600-mutant melanoma.

FIG 1.

PFS in (A) all patients, (B) patients in the encorafenib plus binimetinib arm according to baseline LDH levels, and (C) patients in the encorafenib plus binimetinib arm who had a low tumor burden (ie, normal LDH levels and < 3 organs involved) at baseline. For (A), HR was analyzed using stratified Cox regression model. HR, hazard ratio; LDH, lactate dehydrogenase; NE, not evaluable; PFS, progression-free survival.

FIG 2.

OS in (A) all patients, (B) patients in the encorafenib plus binimetinib arm according to baseline LDH levels, and (C) patients in the encorafenib plus binimetinib arm who had a low tumor burden (ie, normal LDH levels and < 3 organs involved) at baseline. For (A), HR was analyzed using a stratified Cox regression model. HR, hazard ratio; LDH, lactate dehydrogenase; NE, not evaluable; OS, overall survival.

FIG 3.

(A) OS in subgroups for encorafenib plus binimetinib versus vemurafenib. The Cox proportional hazards model is unstratified. (B) Proportion of patients treated with encorafenib plus binimetinib by duration of response. AJCC, American Joint Committee on Cancer; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; LDH, lactate dehydrogenase; OS, overall survival.

FIG A1.

CONSORT diagram. ^aSome patients were ineligible for more than one reason. ^bPrimary reason. ^cOngoing at the time of data cutoff (September 15, 2020). AE, adverse event.

FIG A2.

OS in subgroups for encorafenib plus binimetinib versus encorafenib. The Cox proportional hazards model is unstratified. AJCC, American Joint Committee on Cancer; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; LDH, lactate dehydrogenase; OS, overall survival.

FIG A3.

(A) PFS in the encorafenib plus binimetinib arm by response status at 6 months. (B) OS in the encorafenib plus binimetinib arm by response status at 6 months. Patients are classified on the basis of their response status at 6 months (the landmark time). The number of patients at risk at baseline excludes patients who had an event or were censored at 6 months. HR, hazard ratio; OS, overall survival; PFS, progression-free survival.