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Combination of BRAF and MEK Inhibitors Improves Survival in Advanced Melanoma

TOP - October 2014, Vol 7, No 4

Combination therapy with a BRAF inhibitor and an MEK inhibitor improves outcomes in advanced BRAF-positive melanoma, according to two phase 3 studies presented at the 2014 Congress of the European Society for Medical Oncology (ESMO). These studies support the hypothesis that inhibition of both BRAF and MEK will improve survival in melanoma by overcoming the mechanism of acquired resistance to vemurafenib, which is thought to be reactivation of cell growth through MEK.

In the CoBRIM study, first-line treatment of advanced melanoma with the combination of vemurafenib + cobimetinib (not approved by the US Food and Drug Administration [FDA]) improved progression-free survival (PFS) and overall response rate (ORR) versus vemurafenib alone.1 In the COMBI-v study, the FDA-approved combination of dabrafenib + trametinib improved overall survival (OS) compared with vemurafenib alone.2

CoBRIM Study
CoBRIM was a phase 3, double-blind, placebo-controlled study of vemurafenib/cobimetinib versus vemurafenib plus placebo in previously untreated BRAFV600 mutation–positive metastatic melanoma. The study randomized 495 patients to either arm in a 1:1 ratio, with PFS as the primary end point.

“This study is very important, as it shows that using 2 drugs together to turn off 2 individual proteins [BRAF and MEK] that interact and bind to each other in the cell gives improved results for patients. This is a fundamental concept that could have far-reaching consequences for how we treat many cancers,” said lead author Grant McArthur, PhD, head of the Cancer Therapeutics Program at the Peter MacCallum Cancer Centre in Melbourne, Australia.

Median investigator-assessed PFS was 6.2 months for the vemurafenib arm versus 9.9 months for the combination arm, a highly statistically significant difference (P < .0001) representing a 49% reduction in risk of progression or death for the combination therapy arm.

The ORR was significantly better with the combination therapy: 68% versus 45%; complete response (CR) rates were 10% versus 4%, respectively. An interim analysis of OS suggested that the risk of death would be reduced by 35% in patients who received both drugs versus those who got vemurafenib plus placebo (P < .05).

The combination was tolerable, McArthur said, with a manageable adverse event profile consistent with previous reports. Gastrointestinal (GI) 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 on the combination therapy. Hyperkeratosis was significantly lower with the combination, because MEK inhibition reduces this side effect of vemurafenib, McArthur explained. Creatine phosphokinase level was increased with the combination, but other adverse events were similar in the two 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,” McArthur stated. “We anticipate that the combination of a BRAF and MEK inhibitor will become a new standard treatment for advanced BRAF-mutant melanoma.”

COMBI-v Study
COMBI-v is an ongoing open-label phase 3 study of BRAFV600-mutated advanced melanoma in treatment-naive patients randomized to receive the combination of dabrafenib + vemurafenib (MEK inhibitor and BRAF inhibitor). The study enrolled 704 patients with advanced or metastatic melanoma and good performance status. In COMBI-v, brain metastases were allowed but only if treated and stable for at least 12 weeks.

The combination therapy reduced the risk of death by 31%, according to a preplanned interim analysis of OS presented at ESMO. Median overall survival is not yet reached in the combination arm and was 17.2 months in the vemurafenib-alone arm (P = .005).

“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 our patients,” said lead author Caroline Robert, MD, head of dermatology at the Institut Gustave Roussy in Paris, France.

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. Robert presented the results of the interim analysis, which is now considered the final analysis, she said.

Additionally, the combination reduced the risk of disease progression by 44% versus vemurafenib monotherapy. Median PFS was 11.4 months for the combination versus 7.3 months for vemurafenib (P < .001). ORR was 64% versus 51%, respectively, a significant difference of 13% (P < .001). CR was 13% versus 8%, respectively, and partial response was 51% versus 44%, respectively. Duration of response was almost twice as long for the combination arm: 13.8 months versus 7.5 months.

The rate of adverse events was similar in the 2 arms. The combination was associated with increased incidence of pyrexia and decrease in left ventricular ejection fraction compared with vemurafenib alone, while 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,” Robert commented.


  1. McArthur G, Ascierto PA, Larkin J, et al. Phase 3, double-blind, placebo-controlled study of vemurafenib versus vemurafenib + cobimetinib in untreated BRAFV600 mutation-positive patients with unresectable locally advanced or metastatic melanoma. Presented at: 2014 Congress of the European Society for Medical Oncology; September 26-30, 2014; Madrid, Spain. Abstract LBA5.
  2. Robert C, Karaszewska B, Schachter J, et al. COMBI-v: a randomized, open-label, phase III study comparing the combination of dabrafenib (D) and trametinib (T) with vemurafenib (V) as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. Presented at: 2014 Congress of the European Society for Medical Oncology; September 26-30, 2014; Madrid, Spain. Abstract LBA4.

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