Skip to main content
Premium Trial:

Request an Annual Quote

Phase III Studies Show Benefit of MEK/BRAF Inhibition in BRAF Mutated Melanoma Patients

Premium

Originally published Sept. 30.

NEW YORK (GenomeWeb) – A study of nearly 500 melanoma patients with Stage IIIC to IV melanoma with BRAF V600 mutations lived a median of 3.7 months longer without their disease progressing when they received Roche/Genentech's Zelboraf (vemurafenib) in combination with cobimetinib compared to those treated with only Zelboraf.

The study published in the New England Journal of Medicine and sponsored by Roche screened more than 1,000 patients from January 2013 through January 2014, and enrolled 495 with BRAF V600E-mutated metastatic melanoma. Patients were randomized to receive Zelboraf plus the investigational drug cobimentinib, or Zelboraf plus a placebo. The primary endpoint was progression-free survival; secondary endpoints included overall survival, objective response rate, and progression-free survival gauged by independent review.

Zelboraf is a BRAF inhibitor approved by the US Food and Drug Administration in 2011 for melanoma patients with BRAF mutated tumors. Roche/Genentech's investigational cobimetinib, being developed under a collaboration agreement with Exelixis, inhibits MEK, a kinase in the RAS/RAF/MEK/ERK pathway and has shown efficacy in BRAF-mutated melanoma. Roche has submitted data from this recently published Phase III trial, called coBRIM, to the European Medicines Agency, and subsidiary Genentech is planning to submit a new drug application with US regulatory authorities later this year.

Although the survival data from coBRIM aren't mature, researchers noted that the results were encouraging enough to suggest that the combination of a MEK and BRAF inhibitor yielded better patient outcomes in BRAF-mutated melanoma patients than did treatment with a single BRAF inhibitor. "The combination of vemurafenib and cobimetinib, as compared with vemurafenib alone, resulted in an improvement in progression-free survival and objective responses, with early evidence of improved overall survival and a somewhat increased toxicity profile, among patients with advanced BRAF-mutated melanoma," researchers led by Antoni Ribas of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, wrote in the NEJM paper.

The study had more than 200 progression events by May for 95 percent statistical power, and the researchers reported findings based on analysis from July of this year. Patients receiving the Zelboraf/cobimetinib combo experienced a median of 9.9 months progression-free survival versus 6.2 months in the Zelboraf arm. At interim analysis, 81 percent of patients in the combination arm had experienced overall survival of nine months compared to 73 percent of patients receiving Zelboraf.

At the time of the interim analysis, the overall survival data hadn't reached statistical significance. In the Zelboraf/cobimetinib arm, 34 patients had died, while 51 of those receiving Zelboraf had died. Moreover, 68 percent of patients receiving Zelboraf and cobimetinib had an objective response compared to 45 percent in the control group. The complete response rate was 10 percent for those receiving the combination and 4 percent in the control arm.

The combination of Zelboraf and cobimetinib caused higher rates of serous retinopathy, diarrhea, nausea, or vomiting, photosensitivity, elevated aminotransferase levels, and an increased creatine kinase level in patients. However, more than 50 percent of these cases were low grade events. Grade 3 events were similar in the two arms, while patients receiving the combination experienced more Grade 4 events.

One example of a Grade 4 event that showed up in 30 percent of patients receiving the combination regimen was elevated creatine kinase levels, which is known to be an adverse effect of MEK inhibitors. The majority of these events were not serious, however. Additionally, the instances of retinopathy were reversible for the most part or managed with a reduction or withdrawal of cobimetinib.

Also published in NEJM was a study funded by GlaxoSmithKline comparing its BRAF/MEK inhibitor combination Tafinlar (dabrafenib) and Mekinist (trametinib) against just the BRAF inhibitor Tafinlar. The study yielded results similar to the one on Zelboraf/cobimetinib combination.

Median progression-free survival was 9.3 months in the Tafinalr/Mekinist arm versus 8.8 months in the Tafinlar arm. Overall response rate was 67 percent and 51 percent, in the combination arm and control group, respectively. At six-month interim analysis, the overall survival rate was 93 percent for the Tafinalr/Mekinist combination versus 85 percent for Tafinlar alone. Final overall survival data is not yet released. The adverse events were similar in the two arms, but the combination group required more dose modifications.

In May 2013, GSK received US regulatory approval for Tafinlar and Mekinist as monotherapies that treat melanoma patients with BRAF V600E or V600K mutations whose tumors have spread and can't be operated on. Then, in January of this year, the US Food and Drug Administration granted accelerated approval to the Mekinist/Tafinlar combination as an option for advanced BRAF-mutated melanoma patients.

"Together with the results of a Phase III trial comparing dabrafenib plus trametinib with dabrafenib alone, these findings provide clear evidence of the benefit of combined MEK and BRAF inhibition," Ribas and colleagues wrote in the paper describing the cobimetinib/Zelbraf study.

The Scan

Not as High as Hoped

The Associated Press says initial results from a trial of CureVac's SARS-CoV-2 vaccine suggests low effectiveness in preventing COVID-19.

Finding Freshwater DNA

A new research project plans to use eDNA sampling to analyze freshwater rivers across the world, the Guardian reports.

Rise in Payments

Kaiser Health News investigates the rise of payments made by medical device companies to surgeons that could be in violation of anti-kickback laws.

Nature Papers Present Ginkgo Biloba Genome Assembly, Collection of Polygenic Indexes, More

In Nature this week: a nearly complete Ginkgo biloba genome assembly, polygenic indexes for dozens of phenotypes, and more.