Improved survival with MEK inhibition in BRAF-mutated melanoma

Massachusetts General Hospital Cancer Center, Boston, USA.
New England Journal of Medicine (Impact Factor: 55.87). 06/2012; 367(2):107-14. DOI: 10.1056/NEJMoa1203421
Source: PubMed


Activating mutations in serine-threonine protein kinase B-RAF (BRAF) are found in 50% of patients with advanced melanoma. Selective BRAF-inhibitor therapy improves survival, as compared with chemotherapy, but responses are often short-lived. In previous trials, MEK inhibition appeared to be promising in this population.
In this phase 3 open-label trial, we randomly assigned 322 patients who had metastatic melanoma with a V600E or V600K BRAF mutation to receive either trametinib, an oral selective MEK inhibitor, or chemotherapy in a 2:1 ratio. Patients received trametinib (2 mg orally) once daily or intravenous dacarbazine (1000 mg per square meter of body-surface area) or paclitaxel (175 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to receive trametinib. Progression-free survival was the primary end point, and overall survival was a secondary end point.
Median progression-free survival was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group (hazard ratio for disease progression or death in the trametinib group, 0.45; 95% confidence interval [CI], 0.33 to 0.63; P<0.001). At 6 months, the rate of overall survival was 81% in the trametinib group and 67% in the chemotherapy group despite crossover (hazard ratio for death, 0.54; 95% CI, 0.32 to 0.92; P=0.01). Rash, diarrhea, and peripheral edema were the most common toxic effects in the trametinib group and were managed with dose interruption and dose reduction; asymptomatic and reversible reduction in the cardiac ejection fraction and ocular toxic effects occurred infrequently. Secondary skin neoplasms were not observed.
Trametinib, as compared with chemotherapy, improved rates of progression-free and overall survival among patients who had metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline; METRIC number, NCT01245062.).

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Available from: Dirk Schadendorf, Oct 04, 2015
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    • "Inhibition of MEK, downstream of BRAF, has been tested as a strategy to bypass resistance. In the METRIC trial [Flaherty et al. 2012b], the MEK-1 and MEK-2 inhibitor, trametinib (Mekinist; GSK, recommended dose: 2 mg once daily) was reported to be superior to standard dacarbazine, although indirect comparisons suggest that the benefit in terms of response rate and progression-free survival is less than with BRAFi. The toxicity profile of trametinib differs from BRAFi (Table 1). "
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    ABSTRACT: Following the discovery that nearly half of all cutaneous melanomas harbour a mutation in the BRAF gene, molecular targeted kinase inhibitors have been developed for the treatment of metastatic melanoma and have dramatically improved outcomes for those patients with BRAF mutant disease, achieving high levels of objective response and prolonging survival. Since 2011, the specific BRAF targeted agents, vemurafenib and dabrafenib, and the MEK inhibitor, trametinib, have been licensed for the treatment of patients with unresectable or metastatic BRAF mutant melanoma. As with other biological targeted agents, these drugs are associated with predictable patterns of adverse events. Proactive toxicity management is important to ensure maximum treatment benefit and avoid unnecessary treatment discontinuation. We review the most common and serious adverse events associated with BRAF targeted agents and suggest management algorithms to guide practitioners in using these drugs effectively in the clinic.
    03/2015; 7(2). DOI:10.1177/1758834014566428
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    • "The pivotal phase III trial, METRIC, enrolled patients with metastatic melanoma and BRAF V600E or BRAF V600K mutations that had not been previously treated with a BRAF or MEK inhibitor. Results showed significant improvements in OS and PFS, with a median PFS of 4.8 months in the trametinib group and 1.5 months in the chemotherapy group [82]. Because of these results, the FDA approved trametinib in May 2013 for the treatment of patients with metastatic melanoma and BRAF V600E or BRAF V600K mutations who had not formerly received BRAF inhibitor treatment. "
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    ABSTRACT: Melanoma is the least common form of skin cancer, but it is responsible for the majority of skin cancer deaths. Traditional therapeutics and immunomodulatory agents have not shown much efficacy against metastatic melanoma. Agents that target the RAS/RAF/MEK/ERK (MAPK) signaling pathway-the BRAF inhibitors vemurafenib and dabrafenib, and the MEK1/2 inhibitor trametinib-have increased survival in patients with metastatic melanoma. Further, the combination of dabrafenib and trametinib has been shown to be superior to single agent therapy for the treatment of metastatic melanoma. However, resistance to these agents develops rapidly. Studies of additional agents and combinations targeting the MAPK, PI3K/AKT/mTOR (PI3K), c-kit, and other signaling pathways are currently underway. Furthermore, studies of phytochemicals have yielded promising results against proliferation, survival, invasion, and metastasis by targeting signaling pathways with established roles in melanomagenesis. The relatively low toxicities of phytochemicals make their adjuvant use an attractive treatment option. The need for improved efficacy of current melanoma treatments calls for further investigation of each of these strategies. In this review, we will discuss synthetic small molecule inhibitors, combined therapies and current progress in the development of phytochemical therapies. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Cancer Letters 01/2015; 359(1). DOI:10.1016/j.canlet.2015.01.016 · 5.62 Impact Factor
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    • "Ipilimumab, a monoclonal anticytotoxic T-lymphocyte-associated antigen 4 antibody, was approved by the FDA in 2011 on the basis of significant improvement in progression-free survival (PFS) and overall survival (OS) compared with gp100 vaccine treatment.4 Recently, mitogen-activated protein kinase (MAPK) pathway inhibitors, including selective BRAF inhibitors (dabrafenib and vemurafenib) and a selective MEK inhibitor (trametinib), have shown significant improvement of PFS and OS over chemotherapy in patients with BRAF mutant melanoma, which led to the approval of these drugs.5–7 Despite these promising new agents, the majority of metastatic melanomas are not curable. "
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    ABSTRACT: The mitogen-activated protein kinase (MAPK) pathway is a critical oncogenic driver signal in a number of malignancies. The discovery of activating mutations in the MAPK pathway has led to the development of MAPK pathway inhibitors. Selumetinib is a potent and selective inhibitor of MEK1 and MEK2, which are essential downstream molecules in the MAPK pathway. Several preclinical and clinical studies have demonstrated the promising antitumor activity of selumetinib. In this review, we discuss the MAPK pathway in melanoma and summarized data from preclinical and clinical studies of selumetinib for advanced melanoma.
    OncoTargets and Therapy 09/2014; 7:1631-9. DOI:10.2147/OTT.S51596 · 2.31 Impact Factor
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