October 2014, Vol 3, No 7
Combo of BRAF and MEK Inhibitors Improves Survival in Advanced MelanomaUncategorized
Combination therapy with a BRAF and a MEK inhibitor improves outcomes in advanced BRAF-positive melanoma, according to 2 phase 3 studies presented at the 2014 ESMO Congress. 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 FDA) improved progression-free survival (PFS) and overall response rate (ORR) versus vemurafenib alone. In the COMBI-v study, the FDA-approved combination of dabrafenib + trametinib improved overall survival (OS) compared with vemurafenib alone.
CoBRIM was a phase 3, double-blind, placebo-controlled study of vemurafenib/cobimetinib versus vemurafenib alone in previously untreated BRAF V600 mutation–positive metastatic melanoma. The study randomized 495 patients to either arm in a 1:1 ratio, with the primary end point of PFS.
“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, MD, PhD, head of the Cancer Therapeutics Program at the 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 highly statistically significant difference (P<.0001) representing a 49% reduction in risk of progression or death for the combination therapy arm.
ORR was significantly better with the combination therapy: 68% versus 45%; complete response (CR) 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 + placebo (P<.05).
The combination was tolerable, MacArthur 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 on the combination therapy. Hyperkeratosis was significantly lower with the combination, because MEK inhibition reduces this side effect of vemurafenib, MacArthur explained. Creatine 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,” MacArthur 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 is an ongoing open-label phase 3 study of BRAF V600–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 OS analysis presented at ESMO 2014. Median OS 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 the Dermatology Unit at the Institut Gustave Roussy, 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. The analysis Robert presented was 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.
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