Melanoma: A model for testing new agents in combination therapies | Ascierto et al. Journal of Translational Medicine 2010 8 38 http content 8 1 38 JOURNAL OF TRANSLATIONAL MEDICINE COMMENTARY Open Access Melanoma A model for testing new agents in combination therapies Paolo A Ascierto 1 Howard Z Streicher2 and Mario Sznol3 Abstract Treatment for both early and advanced melanoma has changed little since the introduction of interferon and IL-2 in the early 1990s. Recent data from trials testing targeted agents or immune modulators suggest the promise of new strategies to treat patients with advanced melanoma. These include a new generation of B-RAF inhibitors with greater selectivity for the mutant protein c-Kit inhibitors anti-angiogenesis agents the immune modulators anti-CTLA4 anti-PD-1 and anti-CD40 and adoptive cellular therapies. The high success rate of mutant B-RAF and c-Kit inhibitors relies on the selection of patients with corresponding mutations. However although response rates with small molecule inhibitors are high most are not durable. Moreover for a large subset of patients reliable predictive biomarkers especially for immunologic modulators have not yet been identified. Progress may also depend on identifying additional molecular targets which in turn depends upon a better understanding of the mechanisms leading to response or resistance. More challenging but equally important will be understanding how to optimize the treatment of individual patients using these active agents sequentially or in combination with each other with other experimental treatment or with traditional anticancer modalities such as chemotherapy radiation or surgery. Compared to the standard approach of developing new single agents for licensing in advanced disease the identification and validation of patient specific and multi-modality treatments will require increased involvement by several stakeholders in designing trials aimed at identifying even in early stages of drug development the most effective way to .
