Vemurafenib plus cobimetinib

Previously untreated. An international phase III trial included 495 patients with previously untreated, unresectable, stage IIIC or stage IV melanoma and BRAF V600 pathogenic variants. Patients were randomly assigned to receive either the combination of vemurafenib (960 mg by mouth every day) and cobimetinib (60 mg by mouth every day for 21 days followed by a 7-day rest period) or vemurafenib plus placebo. The primary end point was investigator-assessed PFS. Crossover at time of PFS was not allowed. Patients were stratified by stage and geographic region. Two interim analyses of OS were prespecified, with the first specified at the time of analysis of the primary end point.[32][Level of evidence B1]

Previously untreated. An international phase III trial included 495 patients with previously untreated, unresectable, stage IIIC or stage IV melanoma and BRAF V600 pathogenic variants. Patients were randomly assigned to receive either the combination of vemurafenib (960 mg by mouth every day) and cobimetinib (60 mg by mouth every day for 21 days followed by a 7-day rest period) or vemurafenib plus placebo. The primary end point was investigator-assessed PFS. Crossover at time of PFS was not allowed. Patients were stratified by stage and geographic region. Two interim analyses of OS were prespecified, with the first specified at the time of analysis of the primary end point.[32][Level of evidence B1]

The median PFS was 9.9 months in patients who received the combination versus 6.2 months in patients treated with vemurafenib plus placebo. The HRprogression or death was 0.51 (95% CI, 0.39–0.68; P = .001).

Previously untreated. An international phase III trial included 495 patients with previously untreated, unresectable, stage IIIC or stage IV melanoma and BRAF V600 pathogenic variants. Patients were randomly assigned to receive either the combination of vemurafenib (960 mg by mouth every day) and cobimetinib (60 mg by mouth every day for 21 days followed by a 7-day rest period) or vemurafenib plus placebo. The primary end point was investigator-assessed PFS. Crossover at time of PFS was not allowed. Patients were stratified by stage and geographic region. Two interim analyses of OS were prespecified, with the first specified at the time of analysis of the primary end point.[32][Level of evidence B1]

The first interim analysis of OS is immature because of the few events in both arms; therefore, median survival was not reached in either study group.

Previously untreated. An international phase III trial included 495 patients with previously untreated, unresectable, stage IIIC or stage IV melanoma and BRAF V600 pathogenic variants. Patients were randomly assigned to receive either the combination of vemurafenib (960 mg by mouth every day) and cobimetinib (60 mg by mouth every day for 21 days followed by a 7-day rest period) or vemurafenib plus placebo. The primary end point was investigator-assessed PFS. Crossover at time of PFS was not allowed. Patients were stratified by stage and geographic region. Two interim analyses of OS were prespecified, with the first specified at the time of analysis of the primary end point.[32][Level of evidence B1]

Rate of withdrawal of therapy caused by adverse events was similar between the groups (13% for patients treated with the combination and 12% for patients treated with vemurafenib only). Six deaths were attributed to adverse events in the combination group, and three deaths were attributed to adverse events in the vemurafenib-only group.

Previously untreated. An international phase III trial included 495 patients with previously untreated, unresectable, stage IIIC or stage IV melanoma and BRAF V600 pathogenic variants. Patients were randomly assigned to receive either the combination of vemurafenib (960 mg by mouth every day) and cobimetinib (60 mg by mouth every day for 21 days followed by a 7-day rest period) or vemurafenib plus placebo. The primary end point was investigator-assessed PFS. Crossover at time of PFS was not allowed. Patients were stratified by stage and geographic region. Two interim analyses of OS were prespecified, with the first specified at the time of analysis of the primary end point.[32][Level of evidence B1]

The incidence of grade 3 to grade 4 adverse events was similar between the groups (62% in patients treated with the combination and 58% in patients treated with vemurafenib alone). Rare, but serious, adverse events included chorioretinopathy, retinal detachment, decreased ejection fraction, and QT prolongation. Hyperproliferative cutaneous events, including cutaneous SCC, were considered to be related to paradoxical activation of the MAPK pathway and occurred less frequently with the addition of the MEK inhibitor.