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FDA Approves Vemurafenib/Cobimetinib Combo for Melanoma

Silas Inman @silasinman
Published: Tuesday, Nov 10, 2015

Dr. Richard Pazdur

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.

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).

References

  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.

 

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View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Advances in™ Melanoma: Exploring BRAF/MEK in Adjuvant and Neoadjuvant SettingsSep 28, 20191.5
Medical Crossfire®: What Does Data Tell Us About How to Optimize Checkpoint Inhibitor Strategies Across Lines of Care for Patients with Melanoma?Nov 30, 20191.5
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