Second targeted combination regime approved for metastatic melanoma

THE JOURNAL OF COMMUNITY AND SUPPORTIVE ONCOLOGY 51 Volume 14/Number 2 R esearchers are increasingly looking to rational combinations of drugs to meet the challenge of resistance to molecularly targeted anticancer therapies. Te treatment of metastatic melanoma was signifcantly advanced with the development of BRAF inhibitors, but is still limited by the short-lived nature of the responses to these drugs and the almost universal occurrence of tumor regrowth. More durable responses could be produced by targeting multiple points in the mitogen-activated protein kinase (MAPK) signaling pathway of which BRAF is a central component. In the fall of 2015, the MEK inhibitor cobimetinib and BRAF inhibitor vemurafenib became the second such combination to receive regulatory approval in the United States following positive results from the international, phase 3, randomized coBRIM trial, which demonstrated the superiority of the combination over singleagent BRAF inhibitor therapy. It also marked the frst US approval for cobimetinib. A total of 495 patients aged 18 years or older, with histologically confrmed, resectable, locally advanced stage IIIC or IV melanoma harboring BRAF V600 mutations (as detected by the Cobas 4800 BRAF v600 Mutation Test) were enrolled at 135 sites in the United States, Canada, Australia, New Zealand, Europe, Russia, Turkey, and Israel from January 2013-January 2014. In addition, patients had measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), as assessed by computed tomography; an Eastern Cooperative Oncology Group (ECOG) Scale performance status score of 0 (fully active and able to carry on all performance without restriction) or 1 (restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature); adequate hematologic, hepatic, renal, and cardiac function; and, in those with brain metastases, at least a 3-week history of stable disease. Patients were randomized 1:1 to receive oral vemurafenib 960 mg twice daily, with either placebo or oral cobimetinib 60 mg once daily (on a 21-day on, 7-day of cycle) until withdrawal of consent, unacceptable toxicity, or disease progression. Randomization was stratifed according to American Joint Committee on Cancer stage and geographic region. Tumor assessments were performed at baseline and every 8 weeks. Baseline patient characteristics were well balanced for age, ECOG performance status, geographic region, and disease stage. More than half of the patients had stage IV M1c melanoma. Te primary endpoint was investigator-assessed progression-free survival (PFS), according to RECIST (version 1.1). According to updated data presented at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO), the combination of cobimetinib and vemurafenib signifcantly improved PFS compared with vemurafenib and placebo (12.3 months vs 7.2 months, respectively; hazard ratio [HR], 0.58; P < .001), and the beneft was observed across all prespecifed patient subgroups. Secondary endpoints included overall survival (OS), confrmed objective response rate (ORR), duration of response (DoR), PFS as assessed by independent review Second targeted combination regime approved for metastatic melanoma