Abstract
We reviewed the literature to assess the efficacy and risk of constitutional, cardiac, gastrointestinal, and dermatological toxicities of combined BRAF plus MEK inhibitors versus BRAF inhibitors alone in patients with metastatic melanoma with BRAF mutations. Searches were conducted in PubMed, Cochrane Database of Systematic Reviews, Google scholar, ASCO, Scopus, and EMBASE for reports published from January 2010 through March 2019. Efficacy, including progression-free survival (PFS) and overall survival (OS) rates, were assessed by hazard ratio (HR); objective response rates (ORR) were assessed by odds ratio (OR). The randomized clinical trials (RCTs) with comparison to vemurafenib monotherapy were included to determine constitutional, gastrointestinal, cardiac, and dermatological toxicities using PRISMA statistical analysis with relative risk (RR) for equal comparison to avoid inclusion bias. Five RTCs comprising 2307 patients were included to assess efficacy, while three of the five RCTs comprising 1776 patients were included to assess adverse events. BRAF plus MEK inhibitor combination therapy demonstrated overall better efficacy compared to BRAF inhibitor monotherapy. Combination therapies appear to have favorable dermatologic side effect profiles, similar constitutional and cardiac profiles, and slightly worse gastrointestinal profiles compares to monotherapy regimens.
Highlights
IntroductionMelanoma is the fifth most common cancer in both men and women in the United States (US)
Melanoma is the fifth most common cancer in both men and women in the United States (US).Survival rates depend largely on the stage of the disease at diagnosis, with 5-year survival rate ranging from approximately 98% for localized disease to only about 23% for metastatic disease with previous traditional chemotherapy regimens [1]
When compared to vemurafenib monotherapy, as performed in the studies by Dummer, Robert, and Ascierto, encorafenib plus binimetinib had a hazard ratio (HR) of 0.54, dabrafenib plus trametinib had a HR of 0.56
Summary
Melanoma is the fifth most common cancer in both men and women in the United States (US). Survival rates depend largely on the stage of the disease at diagnosis, with 5-year survival rate ranging from approximately 98% for localized disease to only about 23% for metastatic disease with previous traditional chemotherapy regimens [1]. Until 2011, treatment for metastatic disease most commonly included chemotherapy with alkylating agents such as dacarbazine and temozolomide, Cancers 2019, 11, 1950; doi:10.3390/cancers11121950 www.mdpi.com/journal/cancers. Cancers 2019, 11, 1950 and/or immune-stimulatory cytokines such as interleukin-2 which provided a small overall survival benefit [2]. Melanomas have a range of gene and protein alterations which are susceptible to therapies targeting the mitogen-activated protein kinase (MAPK) pathway. About 65% of melanomas contain mutations in the RAS–RAF–MEK–ERK pathway.
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