As of June 21, 2013, 128 patients had been treated, comprising 65 patients who had disease progression while receiving vemurafenib and 63 patients who were BRAFi-naïve. Of the 63 BRAFi-naïve patients, 42 (67%) were previously untreated and 21 (33%) had been treated with agents other than a BRAFi. The majority of patients had Stage IV, M1c melanoma at the time of enrollment (vemurafenib-progressors = 82%, BRAFi naïve = 70%). Dose-limiting toxicities were reported in one of six patients in the dose-escalation stage receiving 960 mg of vemurafenib bid and 60 mg of cobimetinib qd on a 21/7-day schedule (Grade 3 QT interval prolongation), and in one of five patients in the dose escalation stage receiving 960 mg of vemurafenib bid and 80 mg cobimetinib qd on a 14/14-day schedule. Dose-limiting toxicities of Grade 3 mucositis and Grade 3 arthralgia were each observed in one of four patients in the dose-escalation stage receiving 960 mg vemurafenib bid and 60 mg cobimetinib qd on a 28/0-day schedule. Two cohorts receiving 60 mg of cobimetinib qd on a 21/7-day schedule with vemurafenib at either 720 mg or 960 mg bid were selected for expansion.
While the study was not designed to measure efficacy, updated results showed a partial or complete response (tumor shrinkage) in many of the patients who had not been previously treated with a BRAF inhibitor. Of the 63 BRAFi-naïve patients, 10% had a complete response, 75% had a partial response, and 13% had stable disease, for an objective response rate of 85%. Most objective responses occurred by the time of the first tumor assessment at 6 weeks. Only two of the BRAFi-naïve patients (3%) had progressive disease. Sixty-one of the 65 patients who had progressed on prior vemurafenib therapy were evaluated for tumor response by RECIST, of which 15% had a partial response, and 43% had stable disease, for an objective response rate of 15%. As of the June 21, 2013 cut-off date, with a median follow-up time of three months, 85.2% of vemurafenib-progressors had already experienced disease progression, and the median progression-free survival (PFS) was 2.8 months. At a median follow-up time of 10 months, 33.3% of BRAFi-naïve patients had experienced disease progression, and the median PFS had not yet been reached.
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