Molecular-target therapy for advanced malignant melanoma].

Malignant melanoma is insensitive to chemotherapy, and standard therapy for metastatic melanoma has been dacarbazine for years. Molecular abnormalities of malignant melanoma, mainly of MAP kinase signals such as BRAF mutation, have been clarified, and molecular target therapy for melanoma has been developed recently. Vemurafenib, an inhibitor for mutated BRAF, has shown its efficacy for the first time, with response rate of more than 50%, and an overall improvement in survival compared with dacarbazine in a phase III study. Skin toxicities including squamous cell carcinoma, are the most severe adverse events. Another BRAF inhibitor, dabrafenib, and a MEK inhibitor, trametinib, have shown excellent efficacy in clinical studies. Melanoma also has high immunogenicity, and cytokines or cell immunotherapy have shown some efficacy. Recently, the importance of immune checkpoints which adjust T-cell activation, such as the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), -B7 or the programmed cell death protein-1(PD1)-PD1 ligand(PDL1), have been clarified. Targeting those immune checkpoints is expected to be effective for enhancing tumor immunity. CTLA-4 antibody ipilimumab has been reported to improve overall survival in two phase III studies. Major adverse events were autoimmune response such as colitis, eruption, liver dysfunction and endocrineopathies. Antibodies to PD1 or PDL1 have shown a higher response rate than those of ipilimumab, and seem to accompany fewer autoimmune responses in phase I studies. These two types of targeting therapy are expected to be standard therapies for melanoma.

Citation

Shunji Takahashi. Molecular-target therapy for advanced malignant melanoma]. Gan to kagaku ryoho. Cancer & chemotherapy. 2013 Jan;40(1):19-25

Mesh Tags

PMID: 23306915

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