Oncologists are now “in the luxury position of having two highly potent agents to treat BRAF V600–mutated melanoma,” noted Christian Blank, MD, PhD, Group Leader of Immunology at The Netherlands Cancer Institute, Amsterdam, who discussed the two papers at the ESMO 2014 Presidential Symposium. However, he added, targeting BRAF alone no longer seems good enough. The initial enthusiasm for BRAF inhibitors was dampened when progression-free survival proved short-lived and relapses occurred rapidly and robustly.

There is strong rationale for dual targeting of the MAP kinase pathway to prevent early tumor “escape” observed during single BRAF inhibition, which is often associated with reactivation of downstream MEK and ERK and ultimately tumor proliferation. Additional blockade of this downstream pathway with MEK inhibitors has now been shown to prolong progression-free survival. In the two trials presented at the ESMO meeting, the addition of trametinib (Mekinist) or cobimetinib to a BRAF inhibitor almost doubled progression-free survival over vemurafenib (Zelboraf) alone, Dr. Blank noted.

Nevertheless, he cautioned, the differences between the arms in these studies were more striking than what was observed in the phase III COMBI-d trial presented at the 2014 ASCO Annual Meeting. In that study, the dabrafenib (Tafinlar)/trametinib combination improved progression-free survival by only 2 weeks over dabrafenib alone (9.3 vs 8.8 months), although the hazard ratio was strong (HR = 0.75; P = .035).¹ In the ESMO trials, response rates were almost identical, and progression-free survival was shorter in coBRIM. The hazard ratios were similar, as were the hazard ratios for overall survival.

Adverse event rates and treatment-related discontinuations were similar as well, but the “quality” of the side effects was different. In both studies, adverse events were mainly driven by those observed with the drugs as single compounds. With both combinations, a reduction in skin toxicity was observed over vemurafenib alone, Dr. Blank noted.

“The only difference was the frequency of serous retinopathy [< 1% in COMBI-v vs 20% in coBRIM], but by trial design, coBRIM mandated more frequent ophthalmologic examinations,” he pointed out, adding that this side effect was transient.

New Standard of Care Emerging

“These trials both confirm the idea of combining BRAF and MEK inhibition to improve progression-free survival and response rates, and what we saw is indicative of an overall survival benefit. I think that, as we have now seen three phase III trials showing benefit from dual MAP kinase pathway targeting, this is becoming the new standard therapy for BRAF-mutated melanoma,” Dr. Blank concluded.

He did suggest that the overall survival benefit from these combinations may ultimately prove less impressive than might be presaged by the progression-free survival differences. If so, there could be several possibilities, including crossover from placebo to the combination, the inclusion of poor-prognosis patients, and rapid deterioration of patients upon progression. It will be “crucial,” he said, to analyze the effect of subsequent treatments in these populations.

At the press briefing, Jeffrey S. ­Weber, MD, of the Moffitt Cancer Center in Tampa, Florida, agreed with the new emerging paradigm and suggested the two BRAF/MEK inhibitor combinations are similar in efficacy.

“The data are more mature from the COMBI-v trial, and dabrafenib plus trametinib is already approved in the United States. This is a terrific combination, but at the end of the day, these are probably relatively similar regimens,” he maintained. “We now have a wealth of options for our patients. It’s great.” ■

Disclosure: Dr. Blank has served as an advisor and received honoraria from both Roche and GlaxoSmithKline. Dr. Weber disclosed receiving honoraria from Bristol-Myers Squibb, Merck, Genentech, AstraZeneca, and Abbvie; clinical research funding from Bristol-Myers Squibb, Merck, GlaxoSmithKline, and Macrogenics (to Moffitt Cancer Center); serving as an advisor to Ichor Therapeutics, Lion Biotechnologies, and Pieris, and owning stock in Celidex Therapeutics, Altor BioScience, and cCAM Biotherapeutics.  

Reference

1. Long GV, Stroyakovsky DL, Gogas H, et al: COMBI-d. ASCO Annual Meeting. Abstract 9011. Presented June 1, 2014.