Short Communication For reprint orders, please contact: reprints@futuremedicine.com Effects of pharmacogenetic variants on vemurafenib-related toxicities in patients with melanoma Andrew KL Goey* , ‡,1 , Mirjam de With ‡,1,2 , Bram C Agema 2 , Esther Oomen-De Hoop 1 , Rajbir K Singh 1 , Astrid AM van der Veldt 1,3 , Ron HJ Mathijssen 1 , Ron HN van Schaik 2 & Sander Bins** ,1 1 Department of Medical Oncology, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands 2 Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam, The Netherlands 3 Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands *Author for correspondence: Tel.: +1 716 845 1300; Fax: +1 716 845 8857; andrew.goey@roswellpark.org **Author for correspondence: Tel.: +31 10 703 48 97; Fax: +31 10 704 1003; s.bins@erasmusmc.nl ‡ Authors contributed equally Aim: The pharmacokinetics and pharmacodynamics of vemurafenib are characterized by a wide interpa- tient variability. Since multiple polymorphic enzymes and drug transporters are involved in vemurafenib pharmacokinetics, we studied associations of polymorphisms on vemurafenib-associated toxicities. Pa- tients & methods: Prospectively collected samples of 97 melanoma patients treated with vemurafenib alone (n = 62) or in combination with cobimetinib (n = 35) were genotyped for ABCB1 (3435C>T), ABCG2 (421C>A, 34G>A) and CYP3A4 (*22, 15389C>T) polymorphisms. Associations between these variants and the incidence of toxicities were studied. Results: CYP3A4*22 was signifcantly associated with increased risk for grade ≥3 nausea, grade 1–4 hyperbilirubinemia, and cutaneous squamous cell carcinoma. ABCB1 3435C>T was a predictor for grade ≥3 toxicity. Conclusion: Genetic variants in CYP3A4 and ABCB1 are associated with vemurafenib-associated toxicities. First draft submitted: 28 July 2019; Accepted for publication: 26 September 2019; Published online: 12 December 2019 Keywords: ABCB1 • ABCG2 • CYP3A4 • melanoma • pharmacogenetics • toxicity • vemurafenib In the USA, melanoma is expected to be the fifth most common cancer in men and women in 2019 [1]. Although patients with localized disease could be cured by surgical excision, the prognosis of metastatic melanoma used to be poor as reflected by 5-year survival rates of 98% (localized melanoma), 64% (regional metastases) and 23% (distant metastases) [1]. These numbers were based on people diagnosed with melanoma between 2008 and 2014. However, with the introduction of immunotherapy and targeted therapy since 2011, the systemic treatment of patients with advanced or metastatic disease changed dramatically [2] and have significantly improved treatment outcome which is illustrated by the increased 2-year survival rate in Dutch patients with advanced melanoma from 23 to 40% in the period of 2012 to 2015 [3]. Current treatment options for patients with disseminated disease include immunotherapy with antibodies targeting PD-1 (e.g., nivolumab [4] and pembrolizumab [5,6]) and/or with the CTLA-4 antibody ipilimumab [7–10], and targeted therapy with combined inhibition of BRAF (e.g., vemurafenib [11], dabrafenib [12], encorafenib [13]) and MEK (e.g., cobimetinib [14], trametinib [15], binimetinib [13]). In 2011, vemurafenib (Zelboraf R  ; Genentech, CA, USA) was the first BRAF inhibitor that was approved by the US FDA for the treatment of unresectable or metastatic melanoma with BRAF V600E mutations at a recommended oral dose of 960 mg twice daily usually in combination with the MEK inhibitor cobimetinib (Cotellic R  ; Genentech) [17]. Compared with vemurafenib monotherapy, the addition of cobimetinib significantly improved progression-free survival (PFS), whereas the incidence of secondary cutaneous cancers decreased [14]. Systemic exposure to vemurafenib is characterized by large interpatient variability with reported coefficients of variation ranging from 32 to 55% [16,18–20]. Exposure-response relationships for vemurafenib have been reported with regards to toxicity and response [18,21]. Pharmacogenomics (2019) 20(18), 1283–1290 ISSN 1462-2416 1283 10.2217/pgs-2019-0101 C  2019 Future Medicine Ltd