Pharmacogenetic investigation of pyrexia in patients treated with dabrafenib alone or in combination with trametinib from five melanoma studies.

e20026 Background: Dabrafenib (D) and trametinib (T) single agents have superior efficacy compared with chemotherapy in metastatic melanoma with BRAF V600E/K mutation, and their use in combination (DT) delays development of resistance compared with D alone. Pyrexia is one of the most common adverse events in patients exposed to D (25–35%) with higher incidence (55–65%) seen in patients treated with DT. However, pyrexia is not associated with baseline clinical characteristics or efficacy, and the mechanism for development of pyrexia is not known. This exploratory pharmacogenetic study aimed to identify germline genetic variants associated with pyrexia by meta-analysis of melanoma patients from five clinical studies. Methods: Blood DNA samples from 1,006 melanoma patients treated with D or DT from clinical studies, BREAK-2, BREAK-MB, BREAK-3, COMBI-d and COMBI-v, were genotyped for genome-wide single nucleotide polymorphisms (SNPs). A total of 6 million SNPs and 50 Human Leucocyte Antigen (HLA) alleles (imp...