The risk of dermatological toxicities of combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma patients: a systematic review and meta-analysis

Background: This meta-analysis was conducted to assess the risk of dermatological toxicities of combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma patients. Methods: We considered relevant prospective randomized phase I, II, and III trials of melanoma patients on the combined BRAF and MEK inhibition versus BRAF inhibition, describing events of rash, photosensitivity reaction (PR), hyperkeratosis (HK), alopecia, cutaneous squamous-cell carcinom(cSCC), skin papilloma(SP), pruritus, and hand-foot syndrome(HFS), as eligible for inclusion. Results: Eight trials comprising 3163 patients were included in the meta-analysis. The relative risks(RRs) of developing all-grade rash with combined BRAF and MEK inhibition versus BRAF inhibition was 1.59 (95%CI, 1.35-1.86, p < 0.00001), HK 0.33(95%CI, 0.16-0.66, p = 0.002), SP 0.09(95%CI, 0.04-0.24, p < 0.00001), alopecia 0.30(95%CI, 0.19-0.48, p < 0.00001), cSCC 0.23(95%CI, 0.17-0.31, p < 0.00001), HFS 0.18(95%CI, 0.13-0.26, p < 0.00001) and PR 0.40(95%CI, 0.26-0.61, p < 0.0001), while the RRs of high-grade dermatological toxicities from all included trials were: rash 0.54(95%CI, 0.20-1.43, p = 0.21), HK 0.18(95%CI, 0.06-0.53, p = 0.002), SP 0.14(95%CI, 0.02-1.16, p = 0.07), alopecia 0.72(95%CI, 0.14-3.62, p = 0.69), cSCC 0.23(95%CI, 0.17-0.33, p < 0.00001), HFS 0.40(95%CI, 0.08-2.06, p = 0.27), and PR 0.14(95%CI, 0.04-0.51, p = 0.003), respectly. Conclusion: Our analysis of data has demonstrated that combined BRAF and MEK inhibitor-based treatment is associated with an increased risk of all-grade rash and a decreased risk of all-grade and high-grade HK, SP, alopecia, cSCC, HFS, and PR compared with single BRAF inhibitor alone in melanoma patients. Appropriate prevention and management are recommended.