Doublet BRAF/MEK inhibition versus single-agent BRAF inhibition in the management of BRAF-mutant advanced melanoma, biological rationale and meta-analysis of published data

Abdel‐Rahman, Omar; Elhalawani, Hesham; Ahmed, Hoda

doi:10.1007/s12094-015-1438-0

Cited by 24 publications

(19 citation statements)

References 31 publications

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“…Pyrexia was also at a higher rate in doublet therapy of BRAF and MEK inhibition. The results were similar to former meta‐analysis …”

Section: Discussionsupporting

confidence: 91%

“…And more patients occurred cutaneous squamous‐cell carcinoma or cutaneous hyperkeratosis . Compared with BRAF inhibition alone, combination therapy delayed the occurrence of acquired resistance and appeared less toxic effects . However, combination therapy was related to a higher incidence of pyrexia and gastrointestinal events (eg, diarrhea, nausea, or vomiting) …”

Section: Introductionmentioning

confidence: 99%

“…15 Compared with BRAF inhibition alone, combination therapy delayed the occurrence of acquired resistance and appeared less toxic effects. 16,17 However, combination therapy was related to a higher incidence of pyrexia and gastrointestinal events (eg, diarrhea, nausea, or vomiting). 13 Based on existing literature, we try to evaluate the effects and clinical relevant adverse events between combination therapy (BRAF and MEK inhibition) and monotherapy (BRAF inhibition alone).…”

Section: Introductionmentioning

confidence: 99%

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Clinical outcomes of BRAF plus MEK inhibition in melanoma: A meta‐analysis and systematic review

Xie

et al. 2019

Cancer Medicine

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Background Melanoma is a potentially fatal malignancy with poor prognosis. Several recent studies have demonstrated that combination therapy of BRAF and MEK inhibition achieved better curative effect and appeared less toxic effects. We conducted a meta‐analysis to evaluate the efficacy and safety between BRAF inhibition plus MEK inhibition combination therapy and BRAF inhibition monotherapy in melanoma patients. Methods We performed the search in PubMed, EMBASE, and the Cochrane Library from January 2010 to January 2019. Inclusion and exclusion of studies, assessment of quality, outcome measures, data extraction, and synthesis were independently accomplished by two reviewers. Revman 5.3 software was used for the meta‐analysis. Results Totally, seven randomized controlled trials involving 3146 patients met our inclusion criteria. Comparing the results of combination therapy and monotherapy, combination therapy significantly improved OS (RR = 1.13; 95% CI, 1.08, 1.19; P < 0.00001), ORR (RR = 1.36; 95% CI, 1.28, 1.45; P < 0.00001), PFS (RR = 0.57; 95% CI, 0.52, 0.63; P < 0.00001) and reduced deaths (RR = 0.78; 95% CI, 0.69, 0.88; P < 0.0001). Skin‐related adverse events such as hyperkeratosis, cutaneous squamous‐cell carcinoma were less compared with monotherapy. However, gastrointestinal events like nausea, diarrhea, and vomiting were at a higher frequency. Conclusion Doublet BRAF and MEK inhibition achieved better survival outcomes over single‐agent BRAF inhibition and occurred less skin‐related events, but gastrointestinal events were more in combination therapy.

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“…Pyrexia was also at a higher rate in doublet therapy of BRAF and MEK inhibition. The results were similar to former meta‐analysis …”

Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Clinical outcomes of BRAF plus MEK inhibition in melanoma: A meta‐analysis and systematic review

Xie

et al. 2019

Cancer Medicine

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“…Prevention of arterial thromboembolism can be achieved by acetylsalicylic acid, but one must take into consideration the increased risk of bleeding . Other kinases inhibitors, such as MEK and BRAF inhibitors (trametinib and its combination with dabrafenib) could also cause hypertension . For many of the agents listed above, LV dysfunction has also been observed, with hypertension thought to contribute to the development of cardiotoxicity.…”

Section: Drug Affecting Primarily the Vascular Systemmentioning

confidence: 99%

“…423,425,426 Other kinases inhibitors, such as MEK and BRAF inhibitors (trametinib and its combination with dabrafenib) could also cause hypertension. 432 For many of the agents listed above, LV dysfunction has also been observed, with hypertension thought to contribute to the development of cardiotoxicity.…”

Section: Inhibitors Of the Vegf Pathwaymentioning

confidence: 99%

Comprehensive review of cardiovascular toxicity of drugs and related agents

Mladěnka

Applová

Patočka

et al. 2018

Medicinal Research Reviews

203

120

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Cardiovascular diseases are a leading cause of morbidity and mortality in most developed countries of the world. Pharmaceuticals, illicit drugs, and toxins can significantly contribute to the overall cardiovascular burden and thus deserve attention. The present article is a systematic overview of drugs that may induce distinct cardiovascular toxicity. The compounds are classified into agents that have significant effects on the heart, blood vessels, or both. The mechanism(s) of toxic action are discussed and treatment modalities are briefly mentioned in relevant cases. Due to the large number of clinically relevant compounds discussed, this article could be of interest to a broad audience including pharmacologists and toxicologists, pharmacists, physicians, and medicinal chemists. Particular emphasis is given to clinically relevant topics including the cardiovascular toxicity of illicit sympathomimetic drugs (e.g., cocaine, amphetamines, cathinones), drugs that prolong the QT interval, antidysrhythmic drugs, digoxin and other cardioactive steroids, beta‐blockers, calcium channel blockers, female hormones, nonsteroidal anti‐inflammatory, and anticancer compounds encompassing anthracyclines and novel targeted therapy interfering with the HER2 or the vascular endothelial growth factor pathway.

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Cardiovascular Adverse Events Associated With BRAF and MEK Inhibitors

et al. 2019

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Key Points Question What is the rate of cardiovascular adverse events among patients with melanoma treated with BRAF and MEK inhibitors compared with patients treated with BRAF inhibitor monotherapy? Findings In this systematic review and meta-analysis of 5 randomized clinical trials including 2317 patients, treatment with BRAF and MEK inhibitors was associated with a higher risk of pulmonary embolism, decrease in left ventricular ejection fraction, and arterial hypertension compared with treatment with BRAF inhibitor monotherapy. The risks of myocardial infarction, atrial fibrillation, and QTc prolongation were similar between groups. Meaning These findings demonstrate an association of cardiovascular adverse events with BRAF and MEK inhibitor therapy, which may guide clinical cardio-oncological management.

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Doublet BRAF/MEK inhibition versus single-agent BRAF inhibition in the management of BRAF-mutant advanced melanoma, biological rationale and meta-analysis of published data

Abstract: Our meta-analysis has demonstrated that combination of MEK/BRAF inhibitors is associated with higher ORR, PFS and OS. However, this comes at the expense of a higher risk of selected toxicities.

Cited by 24 publications

References 31 publications

Clinical outcomes of BRAF plus MEK inhibition in melanoma: A meta‐analysis and systematic review

Clinical outcomes of BRAF plus MEK inhibition in melanoma: A meta‐analysis and systematic review

Comprehensive review of cardiovascular toxicity of drugs and related agents

Cardiovascular Adverse Events Associated With BRAF and MEK Inhibitors

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