Combined BRAF and MEK Inhibition in Patients with unresectable or metastatic cutaneous melanoma: A meta-analysis of randomized controlled trials.

Abstract

e21030 Background: Malignant melanoma is a dangerous disease with increasing incidence. Over the past several years, medical advancements have allowed for markedly improved therapeutic options. In patients with BRAF V600E or V600K mutations, the use of various BRAF inhibitors in combination with MEK inhibitors have been approved for stage III unresectable and metastatic disease. Therefore, we aimed to evaluate the efficacy and safety of this combination in comparison to a single agent BRAF inhibitor. Methods: A comprehensive electronic database search was conducted for all randomized controlled trials (RCTs) comparing the clinical outcomes of combination BRAF inhibitor and MEK inhibitor versus BRAF inhibitor alone in patients with unresectable stage III or stage IV BRAF-mutated malignant melanoma. The primary outcome was progression-free survival (PFS). Secondary outcomes included overall survival (OS), overall response, and various selected adverse events. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) using a random-effects model at the longest follow-up period. Results: We included five RCTs with 2,113 total patients, with a mean age of 55.5 years and 56.1% male. The combination therapy of BRAF and MEK inhibitors showed superior results with regard to PFS (HR 0.57; 95% CI: 0.50-0.67; p < 0.001), OS (HR 0.69; 95% CI: 0.61-0.78; p < 0.001), and overall response (HR 1.32; 95% CI: 1.23-1.43; p < 0.001) when compared to BRAF inhibitor alone. Additionally, patients treated with combination therapy had a lower incidence of cutaneous squamous cell carcinoma (Risk Ratio: 0.22; 95% CI: 0.10-0.47; p < 0.001) and arthralgia (Risk Ratio 0.34; 95% CI: 0.15-0.74; p < 0.001). Patients who received combination therapy, however, had a higher incidence of diarrhea (risk ratio 2.53; 95% CI: 1.05-6.09; p = 0.04) and pyrexia (risk ratio 4.98; 95% CI: 2.27-10.92; p < 0.001). Conclusions: For patients with unresectable stage III malignant melanoma or metastatic malignant melanoma, combination therapy with BRAF inhibitor and MEK inhibitor was associated with superior PFS, OS, overall response, and lower incidence of cutaneous squamous cell carcinoma and arthralgia compared with BRAF inhibitor alone. The combination therapy, however, was associated with a higher incidence of diarrhea and pyrexia.