The discovery and development of small molecule inhibitors of mutant BRAF kinase and MEK kinase have revolutionized the care of patients with melanoma. When used as single agents, the BRAF inhibitors, vemurafenib and dabrafenib, improve progression free and overall survival when compared to chemotherapy with dacarbazine (1, 2). The MEK inhibitor, trametinib, also improves progression-free survival compared to chemotherapy, but achieves a lower response rate at its maximum tolerated dose in a continuous schedule when compared to BRAF inhibitors (3). Therefore, single agent trametinib is generally reserved for patients with intolerance to BRAF inhibitors, an uncommon event.

The identification of mechanisms of resistance to single agent BRAF inhibitors that reactivate the RAF/MEK/ERK pathway (4–6) led to the hypothesis that addition of a MEK inhibitor to a BRAF inhibitor may prevent or delay the emergence of resistance. This has indeed been the case. Three separate phase 3 trials have shown superiority of dual BRAF and MEK inhibition when compared to single agents BRAF inhibition alone (7–9). Dabrafenib combined with trametinib was superior to dabrafenib alone or vemurafenib alone, and vemurafenib and cobimetinib were superior to vemurafenib alone with hazard ratios for progression-free survival favoring the combination arms of 0.75, 0.56, and 0.51, respectively. Moreover, overall survival was also improved with hazard ratios, favoring the combination arms of 0.63, 0.69, and 0.65, respectively. Interesting combination therapy also substantially improved the complete response rate from 4–9 to 10–13% across the three studies.