**14. NRAS inhibitors**

Phase I/II began. In Phase III clinical trials, the dosing regimen was 150 mg of dabrafenib twice daily, which significantly extended the survival to 5.1 months versus 2.7 months with dacarbazine. Hyperkeratosis, headache and joint pain, fatigue, heartburn have been reported as adverse

*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

*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

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

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

events [24].

**13. MEK inhibitors**

acquired resistance.

life [63].

in treatment with BRAF inhibitors [24].

120 Human Skin Cancers - Pathways, Mechanisms, Targets and Treatments

of the safety profiles of dacarbazine and selumetinib [62].

NRAS-mutant melanoma is a common subtype of this disease with a poor prognosis. NRAS is a low-molecular plasma-membrane–associated GTP-binding protein that constitutively activates intracellular signaling through a variety of pathways, most notably the RAS–RAF-MAPK and PI3K-AKT pathways. NRAS mutations activate MAPK signaling to a similar degree as BRAF mutations and rarely co-occur with mutations in the PI3K-AKT pathways, suggesting that mutant NRAS drives this pathway, too. NRAS mutation occurs in approximately 15–20% of melanomas, and it is the second most common oncogenic mutation in this disease [65].

Farnesyltransferase inhibitors (FTIs) showed the most promising therapy targeting the NRAS mutant. FTIs alter post-translational NRAS modification to prevent insertion into the plasma membrane. A Phase II study of FTI R115777 was performed in advanced melanoma and its results showed no evidence of clinical activity despite potent inhibition of FTIs in tumor tissue. The effect of these inhibitors has resulted in a stage of toxicity involving myelosuppression, nausea/vomiting and anorexia. Gajewski et al. concluded that FTIs were originally developed as RAS inhibitors and they affect several signaling pathways with potential outcomes for outof-target toxicity. Multiple farnesylated proteins are involved in signal transduction in cancer. FTIs have been developed as a strategy to inhibit the function of these proteins. FTIs inhibit proliferation of melanoma cell lines. Farnesylated proteins are also important for T cell activation and measurement of effects on T cell function was also pursued [66].

Alternative strategies for a directly targeted NRAS mutant include the use of either antisense oligonucleotides or small interfering RNAs (siRNAs, small interfering RNAs) on the mutant NRAS gene. However, this has proved to be technically very demanding and requires advances in siRNA technology before considering use under clinical conditions. Therefore, NRAS mutant melanomas are currently being treated by MEK inhibitors or by newer types of immunotherapy that are not found in the presence of oncogenic mutation.

The first agent to show robust activity specifically in NRAS-mutant melanoma has been an allosteric inhibitor of MEK1 and MEK2 *binimetinib* **(MEK162, ARRY-162)** developed by Array BioPharma. As part of a combined study of BRAF and NRAS mutant melanoma patients, 30 metastatic melanoma patients whose tumors harbored a NRAS mutation were enrolled and treated with binimetinib. The objective response rate was 21% and the progression-free survival was 3.7 months. Further study in this patient population will be necessary to confirm its clinical activity in comparison to other standard therapies. While prospective data with trametinib in NRAS mutant melanoma patients is not available, early retrospective data from ongoing clinical studies suggests that trametinib may have activity in a subset of NRAS mutant melanoma patients [67].

**16. Combination immunotherapy and targeted therapy**

resolved [74].

trametinib [75].

is on-going [76].

this patient population [42].

Studies about combinations of anti-PD-1/PD-L1 agents with other immunotherapeutic agents are currently conducted in treatment of multiple tumor types. Targeting immune checkpoints such as PD-1, PDL-1 and CTLA-4 has achieved remarkable benefit in multiple cancers by blocking immunoinhibitory signals and enabling patients to produce an effective antitumor response. Inhibitors of CTLA-4, PD-1 or PDL-1 administered as single agents have resulted in durable tumor regression in some patients, and combinations of PD-1 and CTLA-4 inhibitors may even enhance antitumor benefit [70]. The combination of ipilimumab and nivolumab was studied in a phase I trial of 86 patients with pretreated malignant melanoma and demonstrated a 40% objective response rate [71]. In Phase II [72] and III studies [73] of this combination used in the treatment of advanced melanoma response rates were quite impressive, but toxicity was notably increased. Almost 83–89% of patients required either topical or oral immunosuppressive therapy for immune-related adverse events (irAE), which led to treatment discontinuation in 36–47% of all patients [72, 73]. However, almost all of the patients (80–100%) treated with immunosuppressive agents had their irAE completely

Possibilities for the Therapy of Melanoma: Current Knowledge and Future Directions

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Recent study by Kim et al. suggests that the addition of MEK inhibitors to targeted and immunotherapy combinations may be associated with increased toxicity; several patients treated by dabrafenib (BRAF inhibitor), trametinib (MEK inhibitor), and ipilimumab (CTLA-4 inhibitor) developed adverse events related to colonic perforation. This condition found in several patients increases the need to further understand the immunomodulatory effects of

Promising results have been presented in a Phase I study in BRAF-mutant advanced melanoma patients receiving atezolizumab (anti PD-L1) combined with vemurafenib (BRAF inhibitor) and cobimetinib (MEK inhibitor), with a response rate of 83%; currently a Phase III study

*Atezolizumab* (Tecentriq, Genentech Oncology) is PD-L1 blocking antibody that previously received FDA accelerated approval for the treatment of locally advanced or metastatic urothelial carcinoma that has progressed after platinum-containing chemotherapy. Atezolizumab was granted FDA approval on October 18, 2016 for the treatment of patients with metastatic non-small cell lung cancer whose disease progressed during or following platinum-containing chemotherapy. Also the combination of atezolizumab with trametinib in patients with BRAF-wild type melanoma demonstrated encouraging results in an early phase study—a Phase III study is planned [77]. Patients with advanced melanoma and high serum lactate dehydrogenase activity present very poor prognosis, regardless of the systemic treatment used [78]. Current research should be focused on understanding the relationship between high serum lactate dehydrogenase activity and the lack of treatment efficacy with immunotherapy and targeted therapy. Probably novel treatment strategies should be developed in
