Sorafenib as a single agent in advanced melanoma have no significant anti-tumor activity T be detected. Only 19% of patients had stable disease with progression-free survival of 16 37 weeks w While 62% had progressive disease with progression-free survival of 11 weeks. No relationship between B RAF mutation status and stable disease was Dapagliflozin observed concerns about the clinical benefit of targeting RAF B treatment of melanoma. The concern over the failure of sorafenib in the hospital led to the first, the development of more effective treatments, and specific inhibitors V600EBRAF targeted. Second Pr clinical trials evaluating whether targeting V600EB RAF alone was sufficient, or whether other members of the MAPK pathway should be targeted in combination for inhibition of melanoma effectively.
Thirdly siRNA targeting by V600EB RAF, MEK1 / 2, ERK1 / 2, cyclin D1, or to determine which member of MAPKpathway to targeted inhibit the development KRN 633 of melanoma, which showed MEK1 / 2 inhibition, the most effective in reducing lung metastases of melanoma development. Fourth, the finding that melanoma with mutated B RAF sensitive to agents targeting MEK in the MAPK pathway are that tumors with wild-type B-RAF or RAS mutation. Fifth, improve sorafenib combination with other drugs for efficacy. Studies sorafenib combined with carboplatin and paclitaxel has shown clinical efficacy only an overall response rate of 26% and myelosuppressive toxicity th Because of the combination with carboplatin and paclitaxel likely.
A Phase II study to evaluate the efficacy of the alkylating agent dacarbazine or temozolomide in combination with sorafenib in advanced stage melanoma patients showed a median progression-free survival with no statistically significant 21.1 weeks for the combination of sorafenib with dacarbazine compared with 11.7 weeks for placebo plus dacarbazine. Unfortunately, no improvement in overall survival was achieved with this combination. A phase III study, the combination of sorafenib with carboplatin and paclitaxel as second-line therapy in patients with unresectable stage III or stage IV melanoma was less promising with a response rate of 12% and 17.9 months, progression-free survival time for placebo plus carboplatin compared with 17.4 months progression-free survival with a combination of sorafenib plus carboplatin.
Sun clinical trials with sorafenib resulted in the conclusion that targeting RAF B can be more effective in combination with other chemotherapeutic agents is pleased t that goal only. Several new compounds have been developed to RAF B, the pharmacological properties improved in comparison with sorafenib, which evaluated in clinical studies target. To go RAF Ren 265 and PLX4032. RAF 265 is a broad spectrum inhibitor of VEGF receptor 2, and the MAP kinase pathway. It inhibits the proliferation of melanoma cells harboring mutations RAF B and to a lesser extent N RAS mutation, wherein substantially no activity t Against cells where these mutations. RAF 265 completely Constantly inhibits the phosphorylation of ERK, and induce regression of melanoma can containing mutant B RAF animal models. PLX4032 is an inhibitor of RAF kinase activity bioavailable with t Times against the RAF V600EB compared to wild-type t