A phase III trial showed that people with previously untreated BRAF V600 mutation-positive advanced melanoma who received the MEK inhibitor cobimetinib plus Zelboraf (vemurafenib) lived significantly longer without their disease worsening or death compared to Zelboraf alone.
The combined therapy reduced the risk of disease worsening or death by half (HR=0.51, 95% CI 0.39-0.68; p<0.0001), with a median PFS of 9.9 months for cobimetinib plus Zelboraf compared to 6.2 months with Zelboraf 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 Zelboraf binds to mutant BRAF, another protein on the pathway, to interrupt abnormal signaling that can cause tumors to grow.
Results from the trial, named coBRIM, were statistically significant across multiple secondary endpoints. The median PFS by independent review committee was 11.3 months for the combination arm compared to 6.0 months for the control arm (HR=0.60, 95% CI 0.45-0.79; p=0.0003). The objective response rate was higher in the combination compared to the control arm (68 vs. 45 percent; p<0.0001).
Overall survival data are not yet mature. The data were presented at ESMO 2014 Congress, and were published in the New England Journal of Medicine.
CoBRIM is an international, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of 60 mg once daily of cobimetinib in combination with 960 mg twice daily of Zelboraf, compared to 960 mg twice daily of Zelboraf alone.
In the study, 495 patients with BRAF V600 mutation-positiv`e unresectable locally advanced or metastatic melanoma and previously untreated for advanced disease were randomized to receive Zelboraf every day on a 28-day cycle plus either cobimetinib or placebo on days 1-21.
Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent. Investigator-assessed PFS was the primary endpoint. In addition to PFS by IRC, ORR and OS, secondary endpoints included duration of response and other safety, pharmacokinetic and quality of life measures.
The safety profile was consistent with a previous study of the combination. The most common adverse events seen in the combination arm included diarrhea, nausea, rash, photosensitivity and lab abnormalities.
The coBRIM trial was sponsored by Genentech, a member of the Roche Group. Cobimetinib was discovered by Exelixis Inc. and is being developed in collaboration with Exelixis. Cobimetinib is also being investigated in combination with several investigational medicines, including an immunotherapy, in several tumor types such as non-small cell lung cancer and colorectal cancer. Zelboraf was co-developed under a 2006 license and collaboration agreement between Roche and Plexxikon, now a member of the Daiichi Sankyo Group.
Roche has submitted the coBRIM data to the European Medicines Agency, and Genentech plans to submit a new drug application to FDA later this year.
Tafinlar Subgroup Data Shows Median OS of 20.0 Months
Updated survival results from a planned analysis of the phase III BREAK-3 study showed 45 percent of patients treated with Tafinlar (dabrafenib) were still alive at two years. The study evaluated 250 patients with BRAF V600E mutant metastatic melanoma.
The data were presented at the ESMO 2014 Congress. Analysis of the study’s progression free survival primary endpoint was reported in 2012. Final analysis of the overall survival endpoint data is expected in 2016.
The trial showed that 45 percent of patients treated with Tafinlar only, were alive at two years compared to 32 percent of patients who began treatment with dacarbazine.
Fifty-nine percent of patients on DTIC treatment whose disease progressed subsequently received Tafinlar treatment and are included in the DTIC control arm results.
At the planned two year follow up, the study showed a median OS of 20.0 months for the Tafinlar arm (95% CI 16.8-24.4) compared to 15.6 months for the DTIC arm (95% CI 12.7-21.2) The hazard ratio of 0.77 (95% CI 0.52-1.13) was not statistically significant.
BREAK-3 is a phase III, randomized, open-label study comparing the efficacy, safety, and tolerability of Tafinlar to DTIC in patients with advanced or metastatic melanoma with a BRAF V600E mutation.
Patients with previously untreated BRAF V600E mutation-positive metastatic melanoma were randomly assigned to receive Tafinlar (150 mg twice daily, orally) or DTIC (1000 mg/m2 intravenously every three weeks). No formal statistical testing was planned for the pre-defined secondary endpoint in this study, due to several study design related factors including the known confounding effect of the patient crossover.
Tafinlar targets BRAF, a key component of the MAPK (mitogen-activated protein kinase) pathway, according to the drug’s sponsor, GlaxoSmithKline. In many types of melanoma, a mutated BRAF protein on the MAPK pathway disrupts normal cellular regulation and promotes increased cell production. Tafinlar binds to the mutated BRAF protein, which may lead to an inhibition of oncogenic signaling, thus inhibiting the proliferation of tumor cells.
