Therapeutic efficacy of combined BRAF and MEK inhibition in metastatic melanoma: a comprehensive network meta-analysis of randomized controlled trials.

// Ruiqin Mai 1,* , Songxia Zhou 2,* , Weixiang Zhong 3,* , Siming Rong 2 , Zhichao Cong 2 , Yunxian Li 2 , Qizhi Xie 2 , Huanming Chen 2 , Xiaoyun Li 2 , Shuhui Liu 2 , Yabin Cheng 4 , Yuanshen Huang 4 , Youwen Zhou 4 and Guohong Zhang 2,4 1 Department of Laboratory Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China 2 Department of Pathology, Shantou University Medical College, Shantou, Guangdong, China 3 Department of Pathology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China 4 Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada * These authors have contributed equally to this work Correspondence to: Youwen Zhou, email: // Guohong Zhang, email: // Keywords : combing BRAF and MEK inhibition, targeted therapy, melanoma Received : May 01, 2015 Accepted : June 03, 2015 Published : June 08, 2015 Abstract Background: Several recent randomized clinical trials have preliminarily demonstrated that initial targeted therapy with combined BRAF and MEK inhibition is more effective in metastatic melanoma (MM) than single agent. To guide therapeutic decisions, we did a comprehensive network meta-analysis to identify evidence to robustly support whether combined BRAF and MEK inhibition is the best initial targeted therapeutic strategy for patients with MM. Methods: The databases of PubMed and trial registries were researched for randomized clinical trials of targeted therapy. Data of outcome were extracted on progression-free survival (PFS), objective response rate (ORR), and overall survival (OS). Network meta-analysis using a Bayesian statistical model was performed to evaluate relative hazard ratio (HR) for PFS and OS, odds ratio (OR) for ORR. Results: Finally, 16 eligible trials comprising 5976 participants were included in this meta-analysis. PFS were significantly prolonged in patients who received combined BRAF-MEK inhibition compared with those who received BRAF inhibition (HR: 0.58, 95%CI: 0.51-0.67, P < 0.0001) or MEK inhibition alone (HR: 0.29, 95%CI: 0.22-0.37, P < 0.0001). Combined BRAF-MEK inhibition also improved the OS over BRAF inhibition (HR: 0.67, 95%CI: 0.56-0.81, P < 0.0001) or MEK inhibition alone (HR: 0.48, 95%CI: 0.36-0.65, P < 0.0001). The ORR was superior in combined BRAF and MEK inhibition comparing with BRAF inhibition (OR: 2.00, 95%CI: 1.66-2.44, P < 0.0001) or MEK inhibition alone (OR: 20.66, 95%CI: 12.22-35.47, P < 0.0001). Conclusions: This study indicates that concurrent inhibition of BRAF and MEK improved the most effective therapeutic modality as compared as single BRAF or MEK inhibition for patients with MM.