Among the pathways deregulated in melanoma, the RAS/RAF/MEK/ERK pathway is an attractive target based on its role in promoting cell proliferation, invasion, and resistance to apoptosis. Beyond the presence of NRAS mutations in approximately 20 % of all melanomas, the basis for this constitutive activation was not well understood. In 2002, the BRAF mutation was discovered in a screen for mutations in the RAF genes. Subsequent biochemical investigations confirmed the role of mutated BRAF in constitutive ERK signaling and in stimulating proliferation and survival. BRAF mutations have been found in approximately 60 % patients, primarily in young individuals with melanoma originating on non-chronically sun-damaged skin [46, 47]. One of the earlier BRAF inhibitors investigated was the multikinase inhibitor sorafenib, which targets BRAF, CRAF, and the VEGF and PDGF receptor tyrosine kinases. As sorafenib was a relatively nonselective BRAF inhibitor, not significant clinical activity was demonstrated in patients with advanced melanoma [48]. However, when combined with chemotherapeutic agents, including carboplatin and paclitaxel, or temozolomide, it showed greater activity leading to phase III trials, which eventually failed both in first line and second line [49, 50]. The failure of sorafenib suggested the need for a more potent and targeted approach. The most common BRAF mutation (in approximately 90 % of clinical pathology samples) is the T1799A point mutation, in which a T  →  A transversion results in an amino acid substitution at position 600 in BRAF, from a valine (V) to a glutamic acid (E). This mutation occurs within the activation segment of the kinase domain, resulting in the protein taking on a constitutive active configuration [51]. Given the prevalence of this mutation in melanoma, there has been an intense interest in selective BRAF inhibitors. In a recent phase I trial, vemurafenib (PLX4032), an oral selective inhibitor of oncogenic BRAF V600E kinase, induced an objective clinical response in 81 % of patients with BRAF V600E mutation-positive melanoma [52]. The most frequent adverse events were arthralgia, rash, nausea, photosensitivity, fatigue, pruritus, and palmar-plantar dysesthesia. Interestingly, squamous cell carcinomas, keratoacanthoma subtype, developed in 31 % of the patients. The majority were resected and none led to discontinuation of treatment. A phase II trial (BRIM 2) involving patients who had received previous treatment for melanoma, positive for the BRAF V600E mutation, showed a best ORR greater than 52 %, with a median duration of response of nearly 7 months, and a median PFS greater than 6 months [53]. A phase III (BRIM 3) trial comparing the efficacy of PLX4032 with that of DTIC in 675 patients with previously untreated, metastatic melanoma positive for the BRAF V600E mutation was published recently [54]. In the interim analysis for OS (see Fig. 30.3) and final analysis for PFS, vemurafenib was associated with a relative reduction of 63 % in the risk of death and of 74 % in the risk of either death or disease progression, as compared with DTIC (P  <  .001 for both comparisons). Response rates were 48 % for vemurafenib and 5 % for DTIC. On August 2011, FDA approved Vemurafenib tablets (Zelboraf, made by Hoffmann –La Roche Inc.) for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an FDA approved test. On February 2012 EMA approved Vemurafenib in monotherapy for the treatment of adult patients with BRAF V600 mutation positive unresectable or metastatic melanoma. The second selective BRAF inhibitor to enter clinical development was GSK2118436. In a phase I/II clinical trial, patients with metastatic melanoma harboring BRAF mutations were accrued [55]. At the two highest doses evaluated, 150 and 250 mg twice daily, objective responses were observed in 10 of 16 patients with BRAF V600E. Of note, five patients with the BRAF V600K mutations were enrolled at the highest doses evaluated, and all had evidence of tumor regression. In addition to seeing responses at various sites of visceral metastatic disease, evidence of regression was observed early in the course of therapy in several patients with small previously untreated brain metastases [56]. The most common toxicities observed were mild-to-moderate fever, fatigue, headache, nausea, and vomiting. A first-line trial comparing GSK2118436 to DTIC in treatment naive metastatic melanoma patients documented that Dabrafenib significantly improved progression free survival compared with Dacarbazine [57].

Although dramatic clinical activity has been shown with single-agent BRAF-targeted therapy, the antitumor effect is of limited duration.

Resistance to BRAF-inhibitor therapy is common and rapidly acquired in the majority of patients [58, 59]. No Mek inhibitor has demonstrated significant clinical activity in BRAF – mutated melanoma in the phase II setting; Selumetinib had a RR of only 10 % in BRAF- mutant melanoma [60] and PD 0325901 was poorly tolerated [61, 62]. In the first published phase III trial Trametinib (GSK 1120212), as compare with chemotherapy improved rates of progression free and overall survival among patients who had metastatic melanoma with a BRAF V600E e V600K mutation [63]. The combination of Dabrafenib and Trametinib increase the rate of pirexia insteed PFS significantly improve [64]. Phase III combination of BRAF and Mek inhibitors studies are currently being tested.

KIT is a receptor tyrosine kinase that plays an important role in proliferation, development, and survival of melanocytes, hematopoietic cells, and germ cells and is ubiquitously expressed in mature melanocytes. Activating mutations and gene amplification of KIT have been found in 39 % of mucosal, 36 % of acral, and 28 % of melanomas that arise in chronically sun-damaged skin [65]. Recent reports, although limited in number, describe dramatic and durable responses to treatment with imatinib mesylate and other KIT inhibitors. Several multicenter phase II trials are currently under way to evaluate KIT-targeted agents, including imatinib, sunitinib, nilotinib, and dasatinib, in melanoma patients whose tumors harbor KIT aberrations. A randomized phase III trial will evaluate nilotinib, a multitarget kinase inhibitor, compared with DTIC as first-line therapy in patients with advanced melanoma harboring KIT mutations. Finally, as with BRAF-targeted therapies, understanding the potential mechanisms of resistance to KIT-targeted therapy is an active area of investigation.