**15. BRAF plus MEK inhibitors**

Therapy with a MEK inhibitor in combination with a BRAF inhibitor is more effective and less toxic than treatment with a BRAF inhibitor alone, and has become the standard of care for patients with BRAF-mutated melanoma. Trametinib, the first MEK inhibitor was approved for the treatment of BRAF-mutated metastatic melanoma not previously treated with BRAF inhibitors, and is also approved in combination with the BRAF inhibitor dabrafenib [68].

The clinical study about combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K–mutant metastatic melanoma demonstrated improved progression-free survival and overall survival. Phase III clinical study enrolled previously untreated patients with BRAF V600E/K–mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib, 150 mg twice daily, plus trametinib, 2 mg once daily, or dabrafenib plus placebo. The primary endpoint was progression-free survival; secondary endpoints were overall response, duration of response, pharmacokinetics and safety. Results showed that 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n = 211) or dabrafenib monotherapy (n = 212). At data cutoff, outcomes remained superior with the combination: 3-year progression-free was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year overall response was 44 versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm. Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year overall response with the combination reached 62% in the most favorable subgroup (normal lactate dehydrogenase) versus only 25% in the unfavorable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use. These data demonstrate that durable survival is achievable with dabrafenib plus trametinib in patients with BRAF V600–mutant metastatic melanoma [69].

The optimal timing and sequence of combination therapy (in particular targeted therapy in combination with immunotherapy) is currently in progress and cannot be precisely predicted for all patients with melanoma. Due to the existence of many potential targets in the immune system many critical questions arise, e.g. which therapy combinations should move forward in development and which patients will benefit from these treatments [70].
