Is combination therapy the next step to overcome resistance and reduce toxicities in melanoma?

In the last few years, several drugs targeting signalling proteins critical for melanoma entered clinical evaluation. In 2011 vemurafenib (Zelboraf®, F. Hoffman-La Roche Ltd.) was approved for BRAF V600-positive melanoma and showed high overall response rates (48–53%). However recent results from a phase II clinical trial also showed that the median duration of response was 6.7 months and median progression free survival was 6.8 months with tumour relapse. Resistance to targeted agents is quite common and understanding of the underlying molecular mechanisms might predict response or failure. The knowledge of the mechanisms involved in intrinsic and acquired resistance to mutated BRAF is increasing swiftly. Subsequently the elucidation of these mechanisms resulted in the development of rational combination therapies to overcome toxicity and resistance. These combination therapies will be discussed.