Regorafenib, C-kit Mutated Malignant Melanoma, 2nd Line Therapy

The incidence of melanoma is rising globally and mortality is increasing faster than most other cancers. Recent advances in the molecular biology of melanoma have uncovered several potential therapeutic targets in melanoma. It has been observed that 81% of melanomas arising from non-chronic sun-damaged skin have an oncogenic BRAF or NRAS mutation, whereas such mutations are far less frequent in chronic sun-damaged skin melanomas, acral melanomas, or mucosal melanomas. In contrast, c-Kit mutations are more common in mucosal and acral melanomas, which can also be accompanied by an increase in c-Kit copy numbers. Asian populations, the most common melanoma subtypes are acral and mucosal melanoma, which comprise greater than 70% of all melanomas, a rate that is much higher than that seen in white populations (6% to 7%). KIT mutations or amplification are reported about 20% in acral or mucosal melanomas (JAMA. 2011;305(22):2327-2334). Therefore, c-Kit mutations are likely the most common kind of genetic mutations in Asians, and the investigation of c-Kit inhibitors is a high priority in this population. Imatinib mesylate (Gleevec, formerly STI571; Novartis Pharmaceuticals, Basel, Switzerland), is a selective inhibitor, targeting Abl as well as c-Kit and the platelet-derived growth factor receptor. Imatinib demonstrated significant activity in patients with metastatic melanoma harboring genetic c-Kit aberrations, with an overall response rate of 29% (J Clin Oncol 2011;29:2904-9) Regorafenib (BAY 73-4506) is a novel, orally active, diphenylurea multikinase inhibitor of VEGFR1-3, c-KIT, TIE-2, PDGFR-β, FGFR-1, RET, RAF-1, BRAF and p38 MAP kinase. Regorafenib provide a significant improved PFS and OS in patients with GIST and colorectal cancer, respectively (Lancet 2013; 381: 295-302, Lancet 2013; 381: 303-12). Especially, inhibitory activity of regorafenib is most effective in c-kit mutated tumors. Therefore, regorafenib has a chance to significant activity in melanoma with c-kit mutations. However, no clinical trials have been published for regorafenib in the patients with melanoma who harbor c-Kit mutations. NCCN recommend ipilimumab, high-dose interleukin-2, and vemurafenib or dabrafenib for BRAF mutated tumor as a preferred regimen, and imatinib for c-kit mutated tumors, dacarbazine, temozolomide, and paclitaxel as other active regimens. In Korea, ipilimumab is not available yet and imatinib for c-kit mutated tumors is not used legally. Thus, regorafenib could be used for c-kit mutated tumor in clinical trial setting.