Combination of BRAF and MEK Inhibitors Improves Survival in Patients with Advanced Melanoma

October 2014, Vol 5 , No 8

Madrid, Spain—Combination therapy with a BRAF inhibitor and a MEK inhibitor improves survival outcomes in patients with advanced BRAF-mutated melanoma, based on results of 2 phase 3 clinical trials presented at the 2014 European Society for Medical Oncology Congress.

These studies support the hypothesis that inhibition of BRAF and MEK will improve survival in melanoma by overcoming the mechanism of acquired resistance to vemurafenib, which is thought to be caused by reactivation of cell growth through MEK.

In the coBRIM trial, first-line treatment of advanced melanoma with the combination of vemurafenib and cobimetinib (approved in Europe) improved progression-free survival (PFS) and overall response rate (ORR) versus vemurafenib alone.

In the COMBI-v study, the FDA-­approved combination of dabrafenib and trametinib improved overall survival (OS) compared with vemura­f­enib alone.

The CoBRIM Study
CoBRIM was a phase 3, double-­blind, placebo-controlled clinical trial of vemurafenib plus cobimetinib versus vemurafenib alone in previously untreated patients with BRAF V600 mutation metastatic melanoma.

A total of 495 patients were randomized to either arm in a 1:1 ratio. The primary end point was PFS.

“This study is very important as it shows that using drugs together to turn off two individual proteins (BRAF and MEK) that interact and bind to each other in the cell, gives much improved results for patients. This is a fundamental concept that could have far-reaching consequences for how we treat many cancers,” said lead investigator Grant McArthur, MBBS, BMedSc, PhD, Head, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, Australia.

Median investigator-assessed PFS was 6.2 months for the vemurafenib arm versus 9.9 months for the combination arm, a significant difference (P <.001) representing a 49% reduction in risk for progression or death with the combination therapy arm.

ORRs were significantly better with the combination therapy compared with monotherapy, at 68% versus 45%; complete response rates were 10% versus 4%, respectively.

An interim OS analysis suggested that the risk of death would be reduced by 35% in patients who received both drugs versus those who received vemurafenib plus placebo (P <.05).

The combination was tolerable, Dr McArthur said, with a manageable adverse event profile consistent with previous reports. Gastrointestinal events were more common with the combination, and these were mostly grade 1 and manageable with medication and dose reduction. Photosensitivity was also more common with the combination therapy. Hyperkeratosis was significantly lower with the combination, because MEK inhibition reduces this side effect of vemurafenib, Dr McArthur said. Creatinine phosphokinase level was increased with the combination, but other adverse events were similar in the 2 arms.

“This study provides clear definitive evidence that cobimetinib combined with vemurafenib results in improved progression-free survival and increased overall response rates. The preliminary overall survival is promising, and the combination was tolerable, consistent with previous trials of this combination,” Dr McArthur stated.

“We anticipate that the combination of a BRAF and a MEK inhibitor will become a new standard treatment for advanced BRAF-mutated melanoma,” he concluded.

The COMBI-v Study
COMBI-v is an ongoing open-label phase 3 clinical trial of 704 treatment-naïve patients with BRAF V600–mutated advanced melanoma and good performance status who are randomized to the combination of the MEK inhibitor dabrafenib and the BRAF inhibitor vemurafenib. Patients with brain metastases were included, but only if these were treated and stable for at least 12 weeks.

An interim analysis showed that the combination therapy reduced the risk of death by 31%, based on a preplanned interim OS analysis presented at the meeting. Median OS is not yet reached in the combination arm and was 17.2 months in the vemurafe­nib-alone arm (P = .005).

Because of the excellent results at the interim analysis, the study was stopped early and patients originally randomized to the vemurafenib arm were allowed to cross over to combination treatment. Lead investigator Caroline Robert, MD, PhD, Head, Dermatology, Institut Gustave Roussy, Villejuif Cedex, France, presented the results of the interim analysis. She said that this analysis is now considered the final analysis.

“These results further corroborate the early preclinical data that more complete blockade of the MAP kinase pathway delays the emergence of resistance, translating into longer survival for the patients,” said Dr Robert.

The combination also reduced the risk of disease progression by 44% versus vemurafenib monotherapy. The median PFS was 11.4 months for the combination versus 7.3 months for vem­urafenib alone (P <.001). The ORR was 64% versus 51%, respectively, a significant 13% difference (P <.001). The complete response rate was 13% versus 8%, respectively, and the partial response rate was 51% versus 44%, respectively.

The duration of response was almost twice as long with the combination arm compared with monotherapy, 13.8 months versus 7.5 months, respectively.

The rate of adverse events was similar in the 2 arms. The combination was associated with increased incidence of pyrexia and a decrease in left-ventricular ejection fraction compared with vemurafenib alone, and the incidence of cutaneous malignancies, hyperproliferative cutaneous events, and photosensitivity was much lower in the combination arm.

“Both of these trials of combination therapy go in the same direction,” Dr Robert commented.

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