Studies Support MEK Inhibitor for BRAF-Positive Melanoma

Source: Clicnial Oncology News, October 2014

Madrid—Adding a MEK inhibitor to a BRAF inhibitor substantially improves outcome in patients with BRAF mutation–positive advanced melanoma, according to two large Phase III studies presented at the European Society for Medical Oncology (ESMO) 2014 Congress. The results of the two studies, although using different types of BRAF and MEK inhibitors, were considered mutually reinforcing.

In both studies, patients with metastatic cutaneous melanoma with a BRAF V600 mutation were randomized to receive a BRAF inhibitor alone or a BRAF inhibitor with a MEK inhibitor. One demonstrated—and the other strongly suggested—a significant improvement in overall survival (OS). In a trial called coBRIM, the BRAF inhibitor vemurafenib (Zelboraf, Genentech) combined with the MEK inhibitor cobimetinib was compared with vemurafenib alone (abstract LBA5_PR). In the other trial, called COMBI-V, the combination of the BRAF inhibitor dabrafenib (Tafinlar, GlaxoSmithKline [GSK]) plus the MEK inhibitor trametinib (Mekinist, GSK) was compared with vemurafenib alone (abstract LBA4_PR).

In coBRIM, the major finding was a 49% reduction in the risk for progression for the combination relative to the BRAF inhibitor alone, but the combination was also associated with a “promising” 35% reduction (P<0.05) in the risk for death, according to the presenting author, Grant McArthur, MD, PhD, the head of the Molecular Oncology Laboratory at Peter McCallum Cancer Centre, in Victoria, Australia. The survival benefit has not yet met the prespecified definition of significance.

The COMBI-V trial, which has more mature data, was stopped at an interim analysis when the primary survival end point was reached. At that time, the risk for death was reduced by 31% (HR, 0.69; P=0.005) for the combination relative to the BRAF inhibitor alone, according to the principal investigator, Caroline Robert, MD, the head of the Dermatology Unit at Institute Gustave Roussy, in Paris. She and Dr. McArthur noted that the addition of a MEK inhibitor was generally well tolerated, leading to an increase in some side effects, such as pyrexia, but a reduction in others, particularly photosensitivity.

Both studies confirm that MEK inhibition slows resistance to BRAF inhibitors. According to the invited ESMO discussant, Christian Blank, MD, PhD, the group leader in immunology at the Netherlands Cancer Institute, in Amsterdam, a combination of BRAF and MEK inhibitors “is becoming the new standard of care” in melanoma with a BRAF V600 mutation, based on the consistency of these data.