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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    • "BRAFV600E gain-offunction mutation is observed in ∼50% of melanomas (Davies et al., 2002). Direct inhibition of BRAFV600E by the RAF inhibitor (RAFi) vemurafenib and inhibition of the downstream MEK and ERK kinases have yielded response rates of more than 50% in melanoma patients with this mutation (Chapman et al., 2011; Flaherty et al., 2012b). At the cellular level, inhibition of the ERK pathway leads to changes in expression of a set of critical cell cycle genes (e.g., CCND1, MYC, FOS) and feedback inhibitors of ERK signaling (e.g., DUSP, SPRY2) (Pratilas et al., 2009). "
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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.
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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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