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Efficacy and safety of BRAF inhibition alone versus combined BRAF and MEK inhibition in melanoma: a meta-analysis of randomized controlled trials.

ABSTRACT: Recent clinical studies have shown that combination therapy of BRAF and MEK inhibition provides more survival benefit than BRAF inhibition monotherapy. However, the adverse events due to BRAF and MEK inhibitors impact the physical comfort and social life of patients. Thus, in this study we have undertaken a meta-analysis of randomized controlled trials to compare the efficacy and adverse events risk between monotherapy and combination therapy. We identified the relevant studies by searching PubMed, EMBASE and Google scholar databases, between the year January 2000 and May 2016. Based on the heterogeneity, the fixed- or random-effects models were employed to analyze the efficacy and the incidence rate of adverse events. In addition, the subgroup analyses were conducted to overcome the effects of heterogeneity. Finally, our study included five RCTs, involving 1730 patients for this meta-analysis. The fixed-effects model demonstrated that combination therapy of BRAF and MEK inhibition provided more survival benefit in terms of ORR, PFS and OS (P < 0.00001). But, the combination therapy also significantly increased the incidences of pyrexia, chills, vomiting, chorioretinopathy, retinal detachment, hypertension, night sweats, increased aspartate aminotransferase and creatine kinase levels (P < 0.05) as compared to monotherapy. But, based on the significantly better survival outcomes, the combined BRAF and MEK inhibition will obviously be the mainstay therapy for the BRAF V600-mutant melanoma. However, a set of adverse events should be paid attention when physicians consider combination therapy.

SUBMITTER: Liu M

PROVIDER: S-EPMC5458282 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Efficacy and safety of BRAF inhibition alone versus combined BRAF and MEK inhibition in melanoma: a meta-analysis of randomized controlled trials.

Liu Mengdong M Yang Xuekang X Liu Jiaqi J Zhao Bin B Cai Weixia W Li Yan Y Hu Dahai D

Oncotarget 20170501 19

Recent clinical studies have shown that combination therapy of BRAF and MEK inhibition provides more survival benefit than BRAF inhibition monotherapy. However, the adverse events due to BRAF and MEK inhibitors impact the physical comfort and social life of patients. Thus, in this study we have undertaken a meta-analysis of randomized controlled trials to compare the efficacy and adverse events risk between monotherapy and combination therapy. We identified the relevant studies by searching PubM ...[more]

PMID: 28416755

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Project description:BackgroundResistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor.MethodsIn this open-label study involving 247 patients with metastatic melanoma and BRAF V600 mutations, we evaluated the pharmacokinetic activity and safety of oral dabrafenib (75 or 150 mg twice daily) and trametinib (1, 1.5, or 2 mg daily) in 85 patients and then randomly assigned 162 patients to receive combination therapy with dabrafenib (150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy. The primary end points were the incidence of cutaneous squamous-cell carcinoma, survival free of melanoma progression, and response. Secondary end points were overall survival and pharmacokinetic activity.ResultsDose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib and 2 mg of trametinib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P=0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P=0.03).ConclusionsDabrafenib and trametinib were safely combined at full monotherapy doses. The rate of pyrexia was increased with combination therapy, whereas the rate of proliferative skin lesions was nonsignificantly reduced. Progression-free survival was significantly improved. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01072175.).

Dataset Information

Efficacy and safety of BRAF inhibition alone versus combined BRAF and MEK inhibition in melanoma: a meta-analysis of randomized controlled trials.

Publications

Efficacy and safety of BRAF inhibition alone versus combined BRAF and MEK inhibition in melanoma: a meta-analysis of randomized controlled trials.

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