Meta-Analysis Confirms Clinical Advantage of BRAF/MEK and PD-1 Inhibitors in Melanoma

Based on a retrospective meta-analysis of clinical trial data, authors of a recent paper in JAMA Oncology concluded that BRAF/MEK and programmed death receptor-1 (PD-1) inhibitors were the most effective treatments that were relatively safe in melanoma.

In the absence of head-to-head clinical trials, researchers at McMaster University retrospectively evaluated data from 15 randomized clinical trials, conducted between 2011 and 2015, to compare the safety and efficacy of systemic first-line treatments for advanced BRAF-mutated melanoma. The most effective treatments that were relatively safe, the authors concluded, were BRAF/MEK and programmed death receptor-1 (PD-1) inhibitors.

Using MEDLINE, Embase, and the Cochrane Registry of Controlled Trials, the authors included phase 2 and 3 trials in their analysis. At least 1 intervention in the study had to be a targeted (BRAF or MEK) or an immune checkpoint inhibitor (PD-1 or cytotoxic T-lymphocyte—associated antigen 4).

Based on these criteria, the final analysis included 15 randomized clinical trials that enrolled 6662 patients who were assigned 1 of 10 treatment strategies. Hazard ratios (HRs) were assigned for overall survival (OS) and progression-free survival (PFS); odds ratios (OR) were assigned for objective response rate (ORR) and serious adverse events (SAEs).

The authors found no significant difference in OS between BRAF/MEK and PD-1 in (HR, 1.02; 95% credible interval [CrI], 0.72-1.45), while BRAF/MEK had a significant advantage for PFS compared with other treatments. BRAF/MEK inhibition was also associated with a higher ORR compared with BRAF inhibition alone (OR, 2.00; 95% CrI, 1.64-2.45). Chemotherapy and PD-1 inhibition were associated with the lowest risk of SAEs.

Based on their findings, the authors concluded that the favorable safety profile of PD-1 inhibitors supports their use as first-line therapy in cases where rapid response to treatment may not be a priority.

“This is the first analysis to draw comparison between targeted and immune therapies for BRAF-mutated melanomas,” senior study author Feng Xie, PhD, associate professor in the Department of Clinical Epidemiology and Biostatistics at McMaster’s Michael G. DeGroote School of Medicine, said in a statement. “Our results will help patients and clinicians choose treatments.”

“While the data in our study represents best available evidence, using more than one kind of immunotherapy shows promise in early outcomes in clinical trials and could change the treatment landscape once longer-term results are published,” Xie added.


Devji T, Levine O, Neupane B, Beyene J, Xie F. Systemic therapy for previously untreated advanced BRAF-mutated melanoma: a systematic review and network meta-analysis of randomized clinical trials [published online October 27, 2016]. JAMA Oncol. doi: 10.1001/jamaoncol.2016.4877.