Molecular targeted therapies have shown promise in the management of various malignancies, including melanoma, with lower toxicity profiles and better overall survival as compared with conventional therapy. The discovery of BRAF mutations in melanoma led to the development of BRAF inhibitors for the targeted therapy of advanced melanoma. However, growing concerns over drug resistance to molecular targeted therapies including BRAF inhibitors, have spurred efforts to elucidate additional molecular targets for the treatment of advanced melanoma.
In 2011 the US Food and Drug Administration approved the selective inhibitor of BRAF, vemurafenib, for patients with malignant melanoma bearing the activating BRAF (V600E) mutation. In a Phase I trial, 81% of patients with V600E-positive metastatic melanoma responded to treatment. Overall, 26 of 32 patients showed a partial response (defined as a decrease by at least 30% in the sum of the largest diameter of each target lesion), including two with complete resolution. Dabrafenib is another selective BRAF inhibitor that has shown significant activity in patients with metastatic melanoma in Phase I/II studies. Further clinical trials are underway with dabrafenib. It is important to note that the BRAF inhibitors, vemurafenib and dabrafenib, are the first treatments to show benefit in patients with metastasis to the brain. In addition, while vemurafenib has been studied in patients with the V600E mutation, studies with dabrafenib are examining activity in non-V600E and V600K mutations.
With limited disease-free survival rates and drug resistance following treatment with BRAF inhibitors, additional treatment options are needed. Efforts are underway to find other targeted therapies within the MAPK pathway that could be used alone or in combination with BRAF inhibitors. There has been significant investigation into MEK inhibition. Phase III trials comparing trametinib, a MEK inhibitor, with chemotherapy in patients with BRAF V600E/K mutant malignant melanoma show improved overall survival and progression-free survival. The combination of dabrafenib and trametinib has shown improved progression-free survival as well as reduction in the rate of secondary cutaneous neoplasms (such as squamous cell carcinoma). Based on the numerous pathways for resistance, MEK inhibition alone is unlikely to be the only answer to BRAF resistance. Nonetheless, MEK inhibitors have shown promise.
Another option being explored for targeted therapy in melanoma is the receptor tyrosine kinase, c-KIT (or CD117). Activating c-KIT mutations have been reported in approximately 20%–30% of certain subtypes of melanoma, including acral melanomas and mucosal melanomas, and melanomas that develop on photodamaged skin. The most common point mutation is L576P in exon 11, but point mutations also occur in exons 13, 17, and 18. Other tumors, including gastrointestinal stromal tumors with c-KIT mutations have been responsive to the tyrosine kinase inhibitor, imatinib. Therefore, Phase II trials were conducted with imatinib in patients with acral or mucosal melanoma or melanomas on chronically sun-damaged skin that harbored KIT mutations or amplifications. Response rates of 16%–23% with a small number of complete long-term responses have been seen, with no difference in response rates between the various melanoma subtypes.
Chakraborty R, Wieland CN, Comfere NI. Molecular targeted therapies in metastatic melanoma. Pharmacogenomics and Personalized Medicine. 2013;6:49-56.