Therapeutic efficacy and safety of combined <em>BRAF</em> and MEK inhibition in patients with malignant melanoma: a meta-analysis

Abstract

BackgroundRecent clinical studies have shown that initial therapy with combined BRAF and mitogen-activated extracellular signal-regulated kinase (MEK) inhibition is more effective in metastatic melanoma than single-agent BRAF inhibitors. However, the response rates with single-agent BRAF are low. Thus, the objective of this study was to conduct a meta-analysis of randomized controlled trials to compare the efficacy and adverse events risk between mono-therapy and combination therapy.Materials and methodsSearches were made in PubMed and EMBASE electronic databases and conference abstracts published by the American Society of Clinical Oncology from 2000 to 2017. Outcomes included overall response, progression-free survival, and overall survival, as well as the incidence rate of adverse events.ResultsEight trials comprising 2,664 patients were included in the meta-analysis. Patients with combined therapies showed superior results compared to those with BRAF inhibitors alone for the following: overall response rate (combined relative risk [RR] =1.34, 95% confidence interval [95% CI]: 1.24–1.45, P<0.00001), progression-free survival (combined hazards ratio [HR] =0.58, 95% CI: 0.52–0.64, P<0.00001), and overall survival rate (combined HR =0.70, 95% CI: 0.62–0.80, P<0.00001). Patients with combination therapies had higher incidence of adverse events including pyrexia (combined RR =2.00, 95% CI: 1.40–2.84), nausea (combined RR =1.41, 95% CI: 1.03–1.94), diarrhea (combined RR =1.50, 95% CI: 1.08–2.06), and vomiting (combined RR =1.87, 95% CI: 01.52–2.31) compared to those with BRAF inhibitors alone.ConclusionThese data suggested that the combined BRAF and MEK inhibition was associated with a significant improvement in overall response, progression-free survival, and overall survival, but increased the incidence of adverse events among the patients with BRAF V600-mutated metastatic melanoma. Further large-scale, high-quality, placebo-controlled, double-blind trials are needed to confirm this conclusion.

Benzylamine and Thenylamine Derived Drugs Induce Apoptosis and Reduce Proliferation, Migration and Metastasis Formation in Melanoma Cells

“…However, dose-limiting side effects are observed, and MEK inhibitors that reduce ERK activation in patients show a low clinical response, probably because MEK inhibition promotes an imbalanced compensatory cell signaling that reduces the therapeutic value of these drugs. Several groups have found that BRAF inhibitor-resistant melanoma cell lines can recover ERK phosphorylation independently of the presence of BRAF inhibitors, and the same remains true for the classic chemotherapeutic drug dacarbazine (DTIC) ( 11 , 13 , 17 , 18 , 20 – 24 ). For these reasons, the development of novel small molecules that could counteract resistance mechanisms constitutes a first line of research in the melanoma field.…”

“…Many patients are excluded from novel therapies only because of fast high-speed progression of the disease before a clinical positive response can be expected ( 9 , 10 ). Taken these facts together, consensus exists in the field suggesting that significant improvements of the overall survival rates of melanoma cohorts require an initial fast response to treatment as an inclusion condition ( 11 ). Long-term survival could then be achieved by an increased rate of complete responses or long-term stabilization of partial responses in what is defined in the melanoma field as consolidation phase ( 2 , 7 , 12 ).…”

“…Long-term survival could then be achieved by an increased rate of complete responses or long-term stabilization of partial responses in what is defined in the melanoma field as consolidation phase ( 2 , 7 , 12 ). The discovery of the frequent BRAF(V600E) mutation in human melanoma tumors offered the first opportunity to develop an oncogene-directed therapy for these patients profiting the use of selective inhibitors of constitutive BRAF activity ( 11 , 13 – 16 ). The fact that melanoma cells express activating mutations in BRAF, but not in A-RAF or C-RAF, allowed the development of the small-molecule drug PLX4032, an orally available and well-tolerated selective BRAF inhibitor.…”

“…Due to the RAS/RAF/MEK/ERK pathway deregulation in ca. 90% of malignant melanomas, MEK is a current target in drug development and in clinical trials ( 11 , 13 , 17 – 19 ). However, dose-limiting side effects are observed, and MEK inhibitors that reduce ERK activation in patients show a low clinical response, probably because MEK inhibition promotes an imbalanced compensatory cell signaling that reduces the therapeutic value of these drugs.…”

MMP-9 as a Candidate Marker of Response to BRAF Inhibitors in Melanoma Patients With BRAFV600E Mutation Detected in Circulating-Free DNA

“…The identification of these mutated genes allowed to develop new therapeutic approaches using selective inhibitors for such altered proteins. Promising results were achieved by the treatment with BRAF inhibitors alone or in combination with MEK inhibitors ( Chen et al, 2017 ; Russo et al, 2017 ). However, the identification of effective biomarker of therapeutic response is still lacking ( Masucci et al, 2017 ; Branca et al, 2018 ; Ross et al, 2018 ; Veenstra et al, 2018 ).…”