The Forecast Is Bright: Recent Advances in Melanoma Treatment / Perspectives prometteuses: Récentes percées dans le traitement des mélanomes

For decades, the medical profession has been in a stalemate regarding malignant melanoma (MM), unable to find therapies to budge the survival rate for patients with advanced disease. The numbers have told a discouraging tale: The 5-year survival rate for patients with stage IV disease is about 15% to 20%, and the 10-year survival ranges from 10% to 15%. Finally, though, the outlook for our patients is brightening. Within the past 3 years the treatment landscape for MM has been transformed by a greater understanding of the molecular pathways involved in carcinogenesis and as a result, novel therapies have flowed from this expanded knowledge. While many previous treatment options have managed to address symptoms, newer therapies have emerged that slow or stop progression, and they actually extend life for patients with advanced disease. One major research challenge has been the inability to find viable drug targets, since you cannot hit the target if you do not know what you are aiming at. Another factor that has come to light with the drug discovery process has been the revelation that not every MM is the same genetically. This has highlighted the next wave in medicine: individualized targeted drug therapy, with its potential for improved patient outcomes. Thanks to a deeper understanding of the molecular pathways that fuel or stall tumor growth, scientists have closed in on a number of genetic and immune targets. For example, a key focus has been on BRAF (B-Raf proto-oncogene), a gene found to be mutated in approximately 50% of MM cases. As a result, research efforts have resulted in new therapies that target this pathway, such as the BRAF inhibitors dabrafenib and vemurafenib. While the results with BRAF inhibitors have been encouraging and at times dramatic, their effect is relatively short lived and these agents can cause a number of adverse events. Hence, another research focus has been to target MEK (mitogen-activated protein kinase), a gene located downstream from BRAF. To this end, the US Food and Drug Administration approved trametinib in 2013. Other MEK inhibitors under investigation include binimetinib and pimasertib. The exciting news is that both BRAF and MEK inhibitors have proven to be much superior to chemotherapy in terms of response rates and progression-free survival. However, even more encouraging is the news that the combination of BRAF and MEK inhibitors has proven even more effective than either agent alone, and these can be administered without drastic increases in adverse effects or toxicity. For example, Robert et al recently showed that combination therapy with dabrafenib and trametinib in patients with previously untreated metastatic MM, with a BRAF V600 mutation, showed greater antitumor activity in the combination group than those who received dabrafenib alone. At 12 months, the overall survival rate was 72% in the combination group versus 65% in the monotherapy group, while progression-free survival was 11.4 months versus 7.3 months, respectively. Moreover, no overall increased toxicity was reported in the combination drug group. As previously mentioned, a stumbling block for both BRAF and MEK inhibitors is that their efficacy tends to wane due to the emergence of resistance several months into treatment. Another challenge is deciding what to do for the 50% of patients who do not have the BRAF mutation. In a small subset of patients (5%), MM displays a C-KIT gene mutation, a mutation typically associated with gastrointestinal tumors. Still, for that subgroup, where MM often develops in acral, mucosal, or chronically sun-damaged skin, targeted therapy may prove effective. Preliminary results from phase 2 trials have shown promising results and low toxicity. Currently under investigation are a number of C-KIT blockers, including imatinib and nilotinib. Yet another approach that offers hope for treating BRAFnegative MM is immunotherapy. Much like letting a guard dog off its leash, these agents work by essentially letting the immune system loose on cancer cells. Immunotherapy targets malignant cells while sparing healthy surrounding tissues. A promising contender in this drug category has been ipilimumab, which targets the T-lymphocyte antigen (CTLA4) that suppresses T-cell function. While ipilimumab is effective on its own, current studies are examining whether ipilimumab could be combined with other therapies to augment tumor response rates. Although one study that studied the combination of vemurafenib and ipilimumab was stopped early due to excessive toxicity, another that explored the pairing of ipilimumab with nivolumab (a PD1 inhibitor) showed much more encouraging results. These more recent findings have demonstrated that combining nivolumab and Editorial 599152 CMSXXX10.1177/1203475415599152Journal of Cutaneous Medicine and Surgery research-article2015