Adding cobimetinib to vemurafenib significantly prolongs progression-free survival in patients with BRAFV600-mutant metastatic melanoma

Results of the phase III coBRIM study evaluating the combination of the MEK inhibitor cobimetinib with the BRAF inhibitor vemurafenib in patients with advanced melanoma demonstrate that dual inhibition of the MEK and BRAF pathways results in a significantly longer progression-free survival (PFS) as compared to BRAF inhibition alone. Interestingly, this clinical advantage did not come at the cost of unacceptable toxicity. Adding cobimetinib to vemurafenib resulted even in significantly less skin toxicity as compared to vemurafenib alone.

Combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. Before the results of this study, it was known that cobimetinib plus vemurafenib could be safely delivered together with highly promising rates of tumour shrinkage, however, until the performance of a well-designed randomised trial, the potential magnitude of this benefit could not be measured. In the ongoing coBRIM study, a total of 495 treatment-naïve patients with BRAFV600-mutation-positive unresectable locally advanced or metastatic melanoma was randomised to receive a 28-day treatment cycle of vemurafenib (960 mg, twice daily), and either cobimetinib or placebo (60 mg daily from days 1-21). The primary endpoint of the study consisted of investigator-assessed progression-free survival (PFS).

Patients in the combination arm of the study showed a significantly improved median PFS of 9.9 months, compared to 6.2 months in the placebo arm. This translates into an impressive 49% reduction in the risk of progression (HR[955CI]: 0.51 [0.39-0.68]; p < 0.0001). Researchers also observed a response rate of 68% in the combination arm versus 45% in the control arm, including a complete response in 10% of patients treated with the combination compared to 4% of patients treated with vemurafenib alone.

The combination therapy did lead to a greater number of grade 3 and above adverse events compared to vemurafenib alone, mainly diarrhea, nausea and photosensitivity. However, treatment with cobimetinib plus vemurafenib also seemed to reduce the incidence of skin-related side-effects known to occur with vemurafenib.

In conclusion, this study shows that using two drugs together to turn off two individual proteins (BRAF and MEK), that interact and bind to each other in the cell, significantly improves the outcome of patients. Researchers anticipate that the combination of a BRAF and a MEK inhibitor will become a new standard treatment for advanced BRAF-mutant melanoma in future.

Reference

McArthur G, Ascierto P, Larkin J, et al. Phase 3, Double-Blind, Placebo-Controlled Study of Vemurafenib Versus Vemurafenib + Cobimetinib in Previously Untreated BRAFV600 Mutation-Positive Patients With Unresectable Locally Advanced or Metastatic Melanoma (NCT01689519). Presented at ESMO 2014; Abstract LBA5.