Safety And Tolerability Of Combined BRAF And MEK Inhibition Versus BRAF Inhibition Alone In Patients With Advanced Melanoma

Background : Compared with BRAF inhibition monotherapy,Significant improvement in survival outcome with the combination therapy of BRAF and MEK inhibition has been shown in advanced melanoma patients.However,the full spectrum of toxic events of BRAF/MEK inhibitor combination therapy was not well characterized.We conducted a comprehensive meta-analysis to state the safety profile of BRAF inhibition plus MEK inhibition combination therapy in metastatic melanoma and identify the exact incidence and RR of both summary and detailed AEs.Methods: We performed the search in PubMed,EMBASE,Cochrane Library,and Clinical Trials.gov to identify relevant studies.Summary incidences,RR and 95%CIs were calculated by using either random effects or fixed effect models according to the heterogeneity of included studies.Results:Overall,five randomized controlled trials involving 2499 patients met our inclusion criteria.For summary toxic events,combination therapy did not significantly increase the risk of any all-grade AEs(grade1-5)(98.31% vs 98.87%;RR 1.00;P= 0.4240),any high-grade AEs(grade3-5)(65.66% vs 58.95%;RR 1.10;P= 0.1029),treatment discontinuation(14.74% vs 12.35%;RR 1.19;P= 0.4825),and treatment-related deaths(0.04% vs 0.00%;RR 1.39;P= 0.6905)compared to monotherapy,except a small but significantly increased risk of any SAEs(39.88% vs35.26%;RR 1.14;P= 0.0428).For detailed toxic events,BRAF plus MEK inhibitor therapy was associated with a significantly lower risk of musculoskeletal AEs,dermatological AEs and secondary neoplasms,but may lead to a significantly higher risk of general disorders,gastrointestinal AEs,cardiovascular AEs and ocular AEs compared with monotherapy.Conclusion:With regard to summary toxic events,the safety and tolerability of the two therapeutic regimens were comparable except a small but significantly increased risk of any SAEs in combination therapy.However,detailed toxic events varied widely between the two groups.Clinicians need to be familiar with the risk of these AEs,recognize them timely,and manage them appropriately.