FDA Approves Vemurafenib/Cobimetinib Combo for Melanoma

The FDA has approved the combination of vemurafenib and cobimetinib as a treatment for patients with metastatic or unresectable BRAF V600E/K mutation-positive melanoma.

Richard Pazdur, MD

The FDA 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 FDA, the median PFS with the combination was 12.3 versus 7.2 months for vemurafenib alone (HR, 0.56; 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 69.6% compared with 50% for vemurafenib alone.

“As we continue to advance our knowledge of tumor biology, we have learned that cancer cells have a remarkable ability to adapt and become resistant to targeted therapies. Combining two or more treatments addressing different cancer-causing targets may help to address this challenge,” Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. “Today’s approval provides a new targeted treatment that, when added to vemurafenib, demonstrates greater benefit than vemurafenib alone in patients with BRAF mutation-positive melanoma.”

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.

There was a 37% reduction in the risk of death with the combination of vemurafenib and cobimetinib compared with vemurafenib alone (HR, 0.63; 95% CI, 0.47-0.85; P = .0019). Updated OS data will be presented later this month at the 2015 Society for Melanoma Research Congress.

In an analysis presented at the 2015 ASCO Annual Meeting,1 the absolute difference in ORR between the two arms was 19.64% (95% CI, 10.95-28.32). The complete response rate in the combination arm was 15.8% versus 10.5% with vemurafenib and placebo (P <.001). The median duration of response was 12.98 months versus 9.23 months, with cobimetinib and placebo, respectively.

In a biomarker analysis from the study, 11% of patients in the coBRIM study were found to have a co-existing baseline mutation in RAS/RAF/RTK. However, these alterations were not found to impact PFS or ORR in patients who received the combination. Additionally, a similar improvement in PFS was seen across subgroups, including those with the V600E and K mutations and for those with normal and elevated serum LDH levels.

In an earlier analysis of the study published in The New England Journal of Medicine,2 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 six deaths related to AEs in the cobimetinib arm and three in the control arm.

“When used in combination, Cotellic and Zelboraf help delay disease progression and help people live significantly longer than with Zelboraf alone,” Sandra Horning, MD, chief medical officer and head of Global Product Development at Genentech, said in a statement. “With this approval, people with this type of deadly and aggressive skin cancer now have a new targeted option.”

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).


  1. Larkin JMG, Yan Y, McArthur GA, et al. Update of progression-free survival (PFS) and correlative biomarker analysis from coBRIM: Phase III study of cobimetinib (cobi) plus vemurafenib (vem) in advanced BRAF-mutated melanoma. J Clin Oncol. 2015;33 (suppl; abstr 9006).
  2. Larkin JMG, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867-1876.