Trametinib plus dabrafenib for unresectable or metastatic melanoma with BRAF V600E or V600K mutations

O n January 9, 2014, the combination of trametinib and dabrafenib was granted accelerated approval by the US Food and Drug Administration for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. Approval of the combination is based on durable response rate observed in an open-label study. Improvements in diseaserelated symptoms and overall survival have not yet been demonstrated for the combination. Both drugs were approved for use as single agents in this setting in May 2013. Trametinib and dabrafenib target diferent tyrosine kinases in the RAS/RAF/MEK/ERK pathway. Trametinib is a reversible inhibitor of MEK1 and MEK2 activation and MEK1 and MEK2 kinase activity. MEK proteins are upstream regulators of the extracellular signalrelated kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E mutations result in constitutive activation of the BRAF pathway, including MEK1 and MEK2. Dabrafenib is an inhibitor of some mutated forms of BRAF kinases; some mutations in the BRAF gene, including BRAF V600E, result in constitutively activated BRAF kinases that stimulate tumor cell growth. Both trametinib and dabrafenib inhibit BRAF V600 mutationpositive melanoma cell growth in vitro and in vivo. Te combination results in greater growth inhibition of BRAF V600 mutation-positive melanoma cell lines and prolonged inhibition of tumor growth in BRAF V600 mutationpositive melanoma xenografts compared with either drug alone. Approval was based on fndings in a trial in which 162 patients with no previous exposure to BRAF or MEK inhibitors were randomized to receive oral trametinib 2 mg (55 patients) or 1 mg (54 patients) once daily plus oral dabrafenib 150 mg twice daily or dabrafenib 150 mg alone (53 patients). Patients had a median age of 53 years, 57% were male, almost of them were white, 66% had Eastern Cooperative Oncology Group performance status of 0 (ie, asymptomatic), 67% had M1c disease, 54% had normal lactate dehydrogenase levels, 8% had a history of brain metastases, and 81% had not received previous therapy for unresectable or metastatic disease. Overall, 85% had BRAF V600E mutations, and 15% had BRAF V600K mutations. Median follow-up was 14 months. Investigator-assessed objective response rate (ORR), the primary endpoint, was 76% in patients receiving trametinib 2 mg plus dabrafenib, including complete response in 9%, compared with 54% in those receiving dabrafenib alone, including complete response in 4%. Median duration of response was 10.5 and 5.6 months, respectively. On independent radiology review committee assessment, ORR was 57% (complete response in 9%), compared with 46% (complete response in 7%), with median duration of response of 7.6 months in both groups. Outcomes were similar in patients with BRAF V600E mutations and BRAF V600K mutations. Patients with abnormal left ventricular ejection fraction, history of acute coronary syndrome within 6 months, current evidence of Class II or higher congestive heart failure (New York Heart Association), history of retinal pigment epithelial detachment or retinal vein occlusion, QTc interval ≥ 480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of glucose-6-phosphate dehydrogenase defciency were excluded from the trial supporting approval of the combination. Te recommended dose of the combination is trametinib 2 mg once daily and dabrafenib 150 mg twice daily. Te most common adverse events of any grade in patients receiving trametinib 2 mg or 1 mg in combination with dabrafenib in the trial supporting approval were pyrexia (71% and 69% vs 26% with dabrafenib alone), chills (58% and 50% vs 17%), fatigue (53% and 57% vs 40%), rash (45% and 43% vs 53%), nausea (44% and 46% vs 21%), and vomiting (40% and 43% vs 15%). Te most common grade 3 or 4 adverse events were pyrexia (5% and 9% vs 0%), nausea (2% and 6% vs 0%), renal failure (7% and 0% vs 0%), back pain (5% and 0% vs 2%), and hemorrhage (5% and 0% vs 0%). Te most common grade 3 or 4 laboratory abnormalities were lymphopenia (22% and 19% vs 6%), neutropenia (13% and 2% vs 6%)increased gamma glutamyltransferase (11% and 17% vs 2%), and hyponatremia (11% and 15% vs 2%). Serious adverse events included bleeding, clot formation, heart failure, skin problems, and eye problems. Te