Abstract
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. 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. 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). 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.
Highlights
Metastatic melanoma (MM) used to be a fatal disease with an average survival of 7 months after diagnosis, since treatment options were limited
Combined BRAF-MEK inhibition improved the overall survival (OS) over BRAF inhibition (HR: 0.67, 95%credibility intervals (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 similar benefit has been found in the objective response rate (ORR), which was superior in combined BRAF and MEK inhibition compared with BRAF inhibition (OR: 2.00, 95%CI: 1.66-2.44, P < 0.0001) or MEK (OR: 20.66, 95%CI: 12.22-35.47, P < 0.0001) inhibition alone
Summary
Metastatic melanoma (MM) used to be a fatal disease with an average survival of 7 months after diagnosis, since treatment options were limited. The cutaneous adverse effects, such as cutaneous squamous cell carcinoma resulted by BRAF-inhibitor– induced paradoxical activation of the MAPK pathway in keratinocytes with upstream activation of signaling by preexisting RAS mutations [6, 7] , which can be blocked with the addition of a MEK inhibition. Combinative targeting the MAPK pathway via BRAF and MEK seem to provide greater clinical efficacy and reduce the adverse effects compared with BRAF inhibition alone. 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.
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