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Review Melanoma Combined BRAF and MEK Inhibition with Vemurafenib and Cobimetinib for Patients with Advanced Melanoma Antonio M Grimaldi, Ester Simeone, Lucia Festino, Vito Vanella and Paolo A Ascierto Melanoma, Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione “G. Pascale”, Napoli, Italy A cquired resistance is the most common cause of BRAF inhibitor monotherapy treatment failure, with the majority of patients experiencing disease progression with a median progression-free survival of 6-8 months. As such, there has been considerable focus on combined therapy with dual BRAF and MEK inhibition as a means to improve outcomes compared with monotherapy. In the COMBI-d and COMBI-v trials, combined dabrafenib and trametinib was associated with significant improvements in outcomes compared with dabrafenib or vemurafenib monotherapy, in patients with BRAF-mutant metastatic melanoma. The combination of vemurafenib and cobimetinib has also been investigated. In the phase III CoBRIM study in patients with unresectable stage III-IV BRAF-mutant melanoma, treatment with vemurafenib and cobimetinib resulted in significantly longer progression-free survival and overall survival (OS) compared with vemurafenib alone. One-year OS was 74.5% in the vemurafenib and cobimetinib group and 63.8% in the vemurafenib group, while 2-year OS rates were 48.3% and 38.0%, respectively. The combination was also well tolerated, with a lower incidence of cutaneous squamous-cell carcinoma and keratoacanthoma compared with monotherapy. Dual inhibition of both MEK and BRAF appears to provide a more potent and durable anti-tumour effect than BRAF monotherapy, helping to prevent acquired resistance as well as decreasing adverse events related to BRAF inhibitor-induced activation of the MAPK-pathway. Combined BRAF and MEK inhibition is the standard of care in patients with advanced BRAF-mutant melanoma. Keywords Metastatic melanoma, BRAF inhibitors, MEK inhibitors, vemurafenib, cobimetinib, combination therapy Disclosure: Antonio M Grimaldi received honoraria from BMS, MSD, Novartis and Roche Genentech, and had consultant/advisory role for MSD and Novartis. Ester Simeone recevied honoraria from BMS, Novartis and Roche Genentech. Ester Simeone had consultant/ advisory role for BMS. Lucia Festino and Vito Vanella have nothing to disclose in relation to this article. Paolo A Ascierto received research founding form BMS, Roche Genentech, Array Biopharma, and had consulting/ advisory role for BMS, Roche Genentech, MSD, Novartis, Array Biopharma, Merck Serono and Pierre Fabre. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. No funding was received for the publication of this article. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: 17 October 2016 Accepted: 18 January 2017 Citation: European Oncology & Haematology, 2017;13(1):61–5 Corresponding Author: Paolo A Ascierto, Melanoma, Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione “G. Pascale”, Via Mariano Semmola, 80131 Napoli, Italy. E: TOU CH MED ICA L MEDIA Metastatic melanoma management has been transformed in the past few years, with the development of new therapeutic options that provide significant survival benefits replacing palliative chemotherapy. One aspect of this advance has been an increased understanding of molecular aberrations in melanoma, in particular, those associated with the mitogen-activated protein kinase (MAPK) pathway. This has resulted in the identification of new oncogenic targets and the development of targeted therapies, including the BRAF inhibitors, vemurafenib and dabrafenib, and the MEK inhibitors, trametinib and cobimetinib. Around 40–60% of cutaneous melanomas have mutations in BRAF that lead to constitutive activation of downstream signalling through the MAPK pathway. 1 The majority of BRAF mutations are V600E (glutamic acid substituted for valine), while 10% are V600K mutations with the remainder involving rare mutations in V600D, V600R or V600M. BRAF V600 mutations significantly increase the catalytic activity of the BRAF protein, leading to constitutive activation and phosphorylation of MEK and ERK in the RAS-RAF-MAPK signalling cascade. 2 BRAF inhibitors and MEK inhibitors specifically inhibit signal transduction by respectively targeting mutated BRAF or MEK. BRAF inhibitors The first BRAF inhibitor to be approved for unresectable or metastatic BRAF V600-mutant melanoma was vemurafenib in 2011. In the phase III BRIM-3 trial of 675 patients with previously untreated metastatic BRAF V600E-mutant melanoma, vemurafenib 960 mg twice daily resulted in longer progression-free survival (PFS) (5.3 versus 1.6 months) and overall survival (OS) (13.6 versus 9.7 months) compared to chemotherapy with dacarbazine. 3 At a median follow up of 7 months, the hazard ratio (HR) for death in the vemurafenib group was 0.37 (95% confidence interval [CI], 0.2–0.55; p<0.001) while the HR for tumour progression was 0.26 (95% CI, 0.20–0.33; p<0.001). In a later analysis with a median follow-up of 12.5 months on vemurafenib and 9.5 months on dacarbazine, vemurafenib maintained significantly longer median PFS (6.9 versus 1.6 months; HR 0.38 [95% CI 0.32–0.46]; p<0.0001) and median OS (13.6 versus 9.7 months; HR 0.70 [95% CI 0.57–0.87]; p=0.0008). 4 A second BRAF inhibitor, dabrafenib, was approved in 2013 having achieved a similar improvement in PFS when compared with dacarbazine (5.1 versus 2.7 months; HR 0.30 [95% CI, 0.18–0.51; p<0.0001) in the phase III BREAK-3 trial. 5 A third BRAF inhibitor, encorafenib (LGX 818) is also in development. 61