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Melanoma Treatment Cobimetinib Helps Prolong Survival in Phase III Trial

Study investigates cobimetinib/vemurafinib combo

New phase III data have shown that the investigational MEK inhibitor cobimetinib (Roche/Exelixis), used in combination with the BRAF inhibitor vemurafinib (Zelboraf, Roche), helped patients with previously untreated BRAF V600 mutation-positive advanced melanoma to live significantly longer without their disease worsening (i.e., progression-free survival [PFS]) compared with patients treated with vemurafinib alone.

Cobimetinib is designed to selectively block the activity of MEK, one of a series of proteins inside cells that make up a signaling pathway that helps regulate cell division and survival. Cobimetinib binds to MEK while vemurafinib binds to mutant BRAF, another protein on the pathway, to interrupt abnormal signaling that can cause tumors to grow.

The phase III CoBRIM trial was an international, randomized, double-blind, placebo-controlled study designed to evaluate the safety and efficacy of cobimetinib in combination with vemurafinib, compared with vemurafinib alone, in 495 patients with BRAF V600 mutation-positive, unresectable, locally advanced or metastatic melanoma, previously untreated for advanced disease. The trial’s primary endpoint was PFS. Secondary endpoints included overall survival, the objective response rate, the duration of response, and other safety, pharmacokinetic, and quality-of-life measures.

In addition to the combination with vemurafinib in melanoma, cobimetinib is being studied in combination with several investigational treatments, including immunotherapy, in numerous tumor types, including non–small-cell lung cancer and colorectal cancer.

In an open-label, dose-finding trial presented in May at the 10th European Association of Dermato Oncology (EADO) Congress, cobimetinib co-administered with vemurafinib achieved an 87% tumor response rate, including a complete response rate of 10%, among BRAF inhibitor-naive patients (n = 63). An additional 10% of patients achieved stable disease. Most of the tumor responses occurred within the first 6 weeks after initiation of treatment. The median PFS in this group was 13.7 months, and 83% of the subjects were alive at 1 year.

For patients who had progressed during treatment with vemurafinib (n = 66), the response and stable disease rates were 15% and 42%, respectively. The median PFS observed with the combination in this group was 2.8 months, and 32% were alive at 1 year.

Across all treated patients (n = 129), the most common adverse events (regardless of attribution to the study drugs) included diarrhea (64%), non-acneiform rash (60%), fatigue (48%), nausea (45%), liver laboratory test abnormality (40%), and photosensitivity/sunburn (40%). The most frequently reported events that were grade 3 or higher were liver laboratory test abnormality (11%), cutaneous squamous cell carcinoma (9%), non-acneiform rash (8%), anemia (7%), joint pain (6%), fatigue (5%), and diarrhea (5%).

Sources: Roche; July 14, 2014; and Roche; May 7, 2014.

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