Efficacy and Adverse Events in Metastatic Melanoma Patients Treated with Combination BRAF Plus MEK Inhibitors Versus BRAF Inhibitors: A Systematic Review

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.

BRAF Inhibitors: Molecular Targeting and Immunomodulatory Actions

“…Paradoxical activation of the MAPK pathway by BRAF inhibitors can increase the risk of the other cutaneous malignancies developing [31]. Combination therapy with a BRAF inhibitor plus a MEK inhibitor is associated with reduced dermatological toxicity, although a slightly worse gastrointestinal adverse event profile, compared with monotherapy [70]. Combination therapy with BRAF inhibitors and some immunotherapeutic agents can also be associated with increased toxicity; in particular, the combination of vemurafenib and ipilimumab (an anti-CTLA4 monoclonal antibody) was associated with marked hepatotoxicity [21,48].…”

A Rare Case of Pituitary Melanoma Metastasis: A Dramatic and Prolonged Response to Dabrafenib-Trametinib Therapy

“…Dual inhibition of the MAPK pathway with the addition of MEKi therapy to BRAFi therapy has been demonstrated in subsequent clinical studies aimed at further improving efficacy results and reducing the toxicities associated with reactivation of the MAPK pathway, including the incidence of secondary malignancies ( 31 ). A scheduled treatment with both BRAFi and MEKi showed a better efficacy overall compared to BRAFi monotherapy ( 32 ). Three BRAFi- MEKi combination treatments (dabrafenib-trametinib, vemurafenib-cobimetinib, and encorafenib-binimetinib) are currently considered the standard treatments for patients with advanced BRAF-mutant melanoma ( 33 – 35 ).…”

Treatment of Advanced Melanoma: Past, Present and Future

“…Moreover, subtypes of AEs differed between these three different BRAF/MEK inhibitor pairs [40], which might be caused by the different immunomodulatory effects in melanoma patients [41]. Indeed, a pre-clinical study in a xenografted mouse melanoma model suggested that dabrafenib, but not vemurafenib, enhances the therapeutic effects of anti-PD1 Abs [41].…”

“…To date, little is known about the mechanisms of AEs developing from melanoma patients treated with BRAF/MEK inhibitors [40,42,43]. Among them, recently, Amagai et al reported a case series with pyrexia developing from advanced melanoma treated with E + B therapy, and suggested that serum levels of soluble CD163 as well as IFN-γ induced chemokines [C-X-C motif chemokine (CXCL9, CXCL10, CXCL11)] were increased in the pyrexia group compared with the non-pyrexia group [42].…”

“…Among them, recently, Amagai et al reported a case series with pyrexia developing from advanced melanoma treated with E + B therapy, and suggested that serum levels of soluble CD163 as well as IFN-γ induced chemokines [C-X-C motif chemokine (CXCL9, CXCL10, CXCL11)] were increased in the pyrexia group compared with the non-pyrexia group [42]. Notably, all of these soluble factors had previously been reported as biomarkers for adult-onset Still's disease (AOSD) [44,45], and the manifestations of AOSD (including pyrexia, transient skin rash, fatigue and arthritis [44,45]) are well-known AEs developing from BRAF/MEK inhibitors [40]. In another report, Irimada et al found a correlation between serum CXCL5 levels and onset of rhabdomyolysis caused by D + T therapy [43].…”