**13. MEK inhibitors**

*Trametinib* (Mekinist® tablets, GlaxoSmithKline) is the first selective allosteric inhibitor of MEK1 and MEK2 (**Figure 3**). In May 2013, it was approved by the FDA as a single agent for the treatment of patients with V600E mutated metastatic melanoma [58]. The recommended daily dose of trametinib is 2 mg orally daily. It has a long half-life, i.e. 4 days at the previously mentioned dosing. In Phase III clinical study, trametinib was well tolerated by patients who most commonly experienced side effects such as diarrhea, asthenia, rash, nausea and vomiting [59]. Development of squamous cell carcinoma as a side effect did not occur at all unlike in treatment with BRAF inhibitors [24].

*Selumetinib*, licensed by Array BioPharma Inc. to AstraZeneca in 2003, inhibits the MEK enzyme in the RAS/RAF/MEK/ERK pathway in cancer cells to prevent the tumor from growing (**Figure 3**). In April 2015, selumetinib was granted Orphan Drug Designation by the U.S. FDA in recognition of the need for new, safe and effective therapies for the uveal melanoma [60]. Uveal melanoma is a rare disease in which cancer cells form in the tissues of the eye. It is the most common primary intraocular malignancy in adults and comprises 5% of all melanomas [61]. In July 2015, AstraZeneca announced that the Phase III clinical SUMIT study of selumetinib in combination with dacarbazine for the treatment of patients with metastatic uveal melanoma did not meet its primary endpoint of progression-free survival. This combination therapy showed an adverse event profile generally consistent with current knowledge of the safety profiles of dacarbazine and selumetinib [62].

Currently, there are being conducted ongoing studies in the elimination of resistance of the MAPK cascade by concomitant administration of inhibitors of MEK and BRAF [52]. This combination of BRAF and MEK inhibitors may prolong progression-free survival, and consequently increase the overall survival of patients. Therapy reactions or responses in patients may be different; the anti-CTLA-4 immunotherapy may lead to long-term response, but not in all patients, whereas targeted drugs may cause responses in most patients, though almost all of them eventually experience relapses due to pre-existing or acquired resistance.

A wide range of mutations are known to prevent effective treatment with chemotherapeutic drugs. Hence, approaches with biopharmaceuticals including proteins, like antibodies or cytokines, are applied [5]. Modern therapeutic approaches in melanoma provide profound and long lasting effects and can even cure some patients. Rational consecutive and combined application of current methods, proper diagnostic and management of related adverse events can prolong life span of patients and meaningfully increase their quality of life [63].

*Cobimetinib* (Cotellic™) was granted FDA approval on November 10, 2015 in combination with vemurafenib (BRAF inhibitor) for the treatment of patients with metastatic melanoma. The approval was based on the effectiveness of cobimetinib plus vemurafenib in a randomized Phase III clinical trial of 495 patients whose tumors had specific mutations in the BRAF gene and who were not candidates for surgery. Patients who received vemurafenib plus cobimetinib had a median progression-free of 12.3 months, compared with 7.2 months in patients who received vemurafenib plus placebo. At 17 months after initiating treatment, about 65% of patients who received the two-drug combination were still alive, compared with 50% of those who received vemurafenib alone [64].
