Encorafenib plus binimetinib

Previously untreated or progression on or after first-line immunotherapy. An international, open-label, phase III trial (COLUMBUS [NCT01909453]) included 577 patients with stage IIIB, IIIC, or IV melanoma and BRAF V600 pathogenic variants. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib (450 mg every day) plus binimetinib (45 mg twice a day), encorafenib monotherapy (300 mg every day), or vemurafenib monotherapy (960 mg twice a day).[33,34] The primary end point was PFS for the combination versus vemurafenib alone as assessed by a blinded IRC with a secondary end point of OS.

Previously untreated or progression on or after first-line immunotherapy. An international, open-label, phase III trial (COLUMBUS [NCT01909453]) included 577 patients with stage IIIB, IIIC, or IV melanoma and BRAF V600 pathogenic variants. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib (450 mg every day) plus binimetinib (45 mg twice a day), encorafenib monotherapy (300 mg every day), or vemurafenib monotherapy (960 mg twice a day).[33,34] The primary end point was PFS for the combination versus vemurafenib alone as assessed by a blinded IRC with a secondary end point of OS.

Approximately 5% of patients had received previous checkpoint inhibitor therapy.

Previously untreated or progression on or after first-line immunotherapy. An international, open-label, phase III trial (COLUMBUS [NCT01909453]) included 577 patients with stage IIIB, IIIC, or IV melanoma and BRAF V600 pathogenic variants. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib (450 mg every day) plus binimetinib (45 mg twice a day), encorafenib monotherapy (300 mg every day), or vemurafenib monotherapy (960 mg twice a day).[33,34] The primary end point was PFS for the combination versus vemurafenib alone as assessed by a blinded IRC with a secondary end point of OS.

With a median follow-up of 16.6 months, the median PFS was 14.9 months (95% CI, 11.0–18.5) with the combination versus 7.3 months (95% CI, 5.6–8.2) with vemurafenib alone. The HRprogression or death was 0.54 (95% CI, 0.41–0.71; 2-sided P < .0001).

Previously untreated or progression on or after first-line immunotherapy. An international, open-label, phase III trial (COLUMBUS [NCT01909453]) included 577 patients with stage IIIB, IIIC, or IV melanoma and BRAF V600 pathogenic variants. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib (450 mg every day) plus binimetinib (45 mg twice a day), encorafenib monotherapy (300 mg every day), or vemurafenib monotherapy (960 mg twice a day).[33,34] The primary end point was PFS for the combination versus vemurafenib alone as assessed by a blinded IRC with a secondary end point of OS.

With a median follow-up of 36.8 months for the secondary end point of OS, the median OS was 33.6 months (95% CI, 24.4–39.2) for patients in the combination arm and 16.9 months (95% CI, 14.0–24.5) for patients treated with vemurafenib alone (HR, 0.61; 95% CI, 0.47–0.79; P < .0001). Subsequent treatments after discontinuation of the study drug were received by 42% of patients in the combination group and 62% of patients in the vemurafenib-alone group.[33,34][Level of evidence A1]

Previously untreated or progression on or after first-line immunotherapy. An international, open-label, phase III trial (COLUMBUS [NCT01909453]) included 577 patients with stage IIIB, IIIC, or IV melanoma and BRAF V600 pathogenic variants. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib (450 mg every day) plus binimetinib (45 mg twice a day), encorafenib monotherapy (300 mg every day), or vemurafenib monotherapy (960 mg twice a day).[33,34] The primary end point was PFS for the combination versus vemurafenib alone as assessed by a blinded IRC with a secondary end point of OS.

The incidence of grade 3 to 4 adverse events was 58% with combination therapy and 63% with vemurafenib alone. Serious adverse events occurred in 34% of the combination group and 37% of the vemurafenib-alone group. The most common adverse events in the combination group included gastrointestinal symptoms and elevation of gamma-glutamyl transferase (GGT), elevation of creatine phosphokinase (CPK), left ventricular dysfunction (8%), and serous retinopathy (20%), mostly grade 1 to 2 (monitoring guidelines are provided in the drug label). Patients who received vemurafenib had more pyrexia and cutaneous toxicities. Study drug discontinuations from adverse events occurred in 15% of patients in the combination group and 17% of patients in the vemurafenib-alone group. No deaths were related to treatment; however, one death from suicide occurred in the combination arm.