European Commission Approves Vemurafenib/Cobimetinib Combo for Melanoma

Michael M. Morrissey, PhD

The European Commission (EC) has approved the combination of vemurafenib (Zelboraf) and cobimetinib (Cotellic) as a treatment for patients with BRAF-positive metastatic or unresectable melanoma, based on an extension in progression-free survival (PFS) in the phase III coBRIM study.

In the data submitted to the EC, the median PFS with the combination was 12.3 months versus 7.2 months for vemurafenib alone (HR, 0.58; P <.001). At a 17-month analysis, 65% of patients receiving the combination remained alive versus 50% for vemurafenib. The objective response rate (ORR) with the combination was 70% compared with 50% for vemurafenib alone.

“The approval of Cotellic by the European Commission for use in combination with vemurafenib is an important milestone in the development of new treatments that can help patients with advanced melanoma,” said Michael M. Morrissey, PhD, president and CEO of Exelixis, the developer of cobimetinib.

The phase III coBRIM study compared the MEK inhibitor cobimetinib plus the BRAF inhibitor vemurafenib to single-agent vemurafenib in previously untreated patients with BRAFV600E/K mutation-positive unresectable locally advanced or metastatic melanoma. In the study, 495 patients were randomized to continuous vemurafenib at 960 mg twice daily plus placebo (n = 248) or cobimetinib at 60 mg once daily on days 1-21 of a 28-day cycle (n = 247).

Patient demographics were well balanced across the two arms for age, ECOG performance status, geographic region, and disease stage. More than half of patients had stage IV, M1c melanoma and the Cobas 4800 BRAF V600 Mutation Test was used to detect BRAF mutations. The primary endpoint for the study was PFS, with secondary endpoints focused on OS, objective response rate (ORR), and duration of response.

OS data from coBRIM were recently presented at the 2015 Society for Melanoma Research Congress. The median OS was 22.3 months with vemurafenib/cobimetinib versus 17.4 months with vemurafenib alone, representing a 30% reduction in the risk of death (HR, 0.70; 95% CI, 0.55-0.90; P = .005). The 1- and 2-year OS rates with the combination were 74.5% and 48.3%, respectively.

In an earlier analysis of the study published in The New England Journal of Medicine, the most frequently reported adverse events (AEs) of all grades reported in the cobimetinib arm versus the control arm included diarrhea (57% vs 28%), nausea (39% vs 24%), photosensitivity (28% vs 16%), increased ALT (24% vs 18%), increased AST (22% vs 13%), increased CPK (30% vs 3%), vomiting (21% vs 12%), and serous retinopathy (20% vs <1%).

Some AEs occurred at lower rates in the combination group, including hair loss (14% vs 29%), hyperkeratosis (10% vs 29%), joint pain (33% vs 40%), cutaneous squamous cell carcinomas (3% vs 11%), and keratoacanthomas (<1% vs 8%). Treatment-related discontinuation rates in the combination and control groups were similar at 13% and 12%, respectively. There were 6 deaths related to AEs in the cobimetinib arm and three in the control arm.

Vemurafenib became the first FDA-approved BRAF inhibitor in 2011. Clinical trials continue to assess vemurafenib plus cobimetinib for patients with melanoma, including a phase II study of the combination as a neoadjuvant therapy for patients with melanoma (NCT02036086). Additionally, a phase Ib study is exploring the combination with the PD-L1 inhibitor atezolizumab for BRAF-positive metastatic melanoma (NCT01656642).