Neue Therapiemöglichkeiten des metastasierten Melanoms

Zusammenfassung

In den letzten beiden Jahren wurden mit dem CTLA-4-Antikörper Ipilimumab und dem selektiven BRAF-Inhibitor Vemurafenib gleich für zwei Medikamente in Phase-III-Studien signifikante Verbesserungen der Gesamtüberlebenszeit bei Patienten mit inoperabler Metastasierung des Melanoms demonstriert. Uns stehen nun neben der Chemotherapie mit der zielgerichteten Therapie und der Immuntherapie zwei neue Therapieoptionen mit unterschiedlichen Wirkmechanismen zur Verfügung. Etwa 50 % der Melanompatienten weisen in ihrem Tumor eine BRAF-V600-Mutation auf und können von einem schnellen und zuverlässigen Wirkungseintritt durch die Therapie mit Vemurafenib profitieren. Allerdings kommt es bei der Mehrzahl der Patienten nach einigen Monaten zur Entwicklung einer Resistenz gegen die BRAF-Inhibition und somit zu einem Wirkverlust. Die Blockade kompensatorischer Mechanismen zur Erhaltung der BRAF-Inhibitor-Sensitivität könnte die wichtigste Indikation für MEK-Inhibitoren werden. Die Wirkung von Ipilimumab setzt erst nach mehreren Wochen langsam und nachhaltig ein. Die klinischen Effekte sind schwerer zu beurteilen, da eine initiale Größenzunahme und neue Metastasen möglich sind. Weiterentwicklungen und Kombinationen innovativer Therapiestrategien werden in zahlreichen klinischen Studien weitere Verbesserungen für die Patienten ermöglichen.

Abstract

During the past two years the CTLA-4 inhibiting antibody ipilimumab and the selective BRAF-inhibitor vemurafenib achieved significant improvements of overall survival for patients with non-resectable advanced melanoma. Remarkably, the targeting of BRAF and the inhibition of T cell activation blockade two differing mechanisms are active against melanoma and led to two approved agents in addition to chemotherapy. In 50 % of the patients melanoma mutated BRAF kinase is expressed and targeting with vemurafenib demonstrates rapid and reliable tumor responses. However, in most patients relapse during treatment due to the development of tumor resistance. The sustained BRAF-inhibitor sensitivity under treatment may be achieved by the combination with a MEK inhibitor. The antitumor effects of ipilimumab manifest later and response is harder to define since initial tumor progression or new lesions can precede tumor regression. Clinical trials employing combinations and further developments of these anti melanoma mechanisms will improve the situation of patients with melanoma in the future.

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