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Targeted Therapies for Melanoma

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European Handbook of Dermatological Treatments

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Abstract

Targeted therapies for melanoma were developed during the last 5 years. Two main types of targets were addressed: kinase molecules in signaling pathways of melanoma cells were targeted by inhibiting small molecules, and molecular checkpoint receptors on T lymphocytes were targeted by inhibiting monoclonal antibodies. Activating BRAF mutations have been detected in nearly 50 % of melanomas, and the two BRAF-inhibiting molecules vemurafenib and dabrafenib proved efficacy in metastatic melanoma with objective tumor remissions in the majority of patients. As a second therapeutic strategy, the inhibition of the downstream molecule MEK has been developed, and efficacy of this treatment approach was likewise proven. The MEK inhibitor trametinib is already approved for clinical application in melanoma. The combination of BRAF and MEK inhibition led to higher objective tumor remissions in up to 80 % of patients carrying the BRAF mutation, and longer survival with progression-free survival times of up to 10 months has been achieved. Further BRAF, MEK, and other kinase inhibitors are in the pipeline for therapeutic application. The second main approach for targeted melanoma therapy is checkpoint blockade by inhibiting antibodies for CTLA-4 and PD-1 receptors. Binding of B7 on antigen-presenting cells to the CTLA-4 receptor on T lymphocytes inhibits T-cell activation, as does binding of PD-L1 and PD-L2 on tumor cells and environmental tissue to the PD-1 receptor on T lymphocytes. These signals can be blocked by antibodies and this leads to continuous activation of T cells. Durable tumor remissions and tumor control have been achieved by using the CTLA-4 antibody ipilimumab and by the PD-1 antibodies nivolumab and pembrolizumab. The combination of ipilimumab and nivolumab resulted in objective tumor remissions in nearly 50 % of patients with metastatic melanoma. For ipilimumab it has been shown that tumor remissions are durable and can be observed for a time period of at least 5 years. Clinical studies during the next years will have to find out how these many new treatment options can be best combined or are best applied in a sequential fashion.

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Authors and Affiliations

  1. Department of Dermatology, Center for Dermatooncology, University Hospital Tübingen, Liebermeisterstrasse 25, 72076, Tübingen, Germany

    Claus Garbe, Friedegund Meier & Thomas K. Eigentler

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  1. Claus Garbe
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  2. Friedegund Meier
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  3. Thomas K. Eigentler
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Correspondence to Claus Garbe .

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Editors and Affiliations

  1. Department of Dermatology, Andreas Syggros Hospital University of Athens, Athens, Greece

    Andreas D. Katsambas  & Clio Dessinioti  & 

  2. University of Rome “G. Marconi”, Rome, Italy

    Torello M. Lotti

  3. Centro Studi per la Ricerca Multidisciplinare Rigenerativa (CSRMR), Rome, Italy

    Torello M. Lotti

  4. Unit of Dermatology, University of Pisa, Pisa, Italy

    Angelo Massimiliano D’Erme

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Garbe, C., Meier, F., Eigentler, T.K. (2015). Targeted Therapies for Melanoma. In: Katsambas, A.D., Lotti, T.M., Dessinioti, C., D’Erme, A.M. (eds) European Handbook of Dermatological Treatments. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-45139-7_150

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