In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
Indication
On May 29, 2013, trametinib (Mekinist) was approved by the U.S. Food and Drug Administration (FDA) for treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutation, as detected by an FDA-approved test.1,2 Concurrent with this approval, FDA approved the THxID BRAF assay (bioMérieux, Inc) for detection of BRAF V600E and V600K mutations. Trametinib is not indicated for treatment of patients who have received prior BRAF inhibitor therapy.
Pivotal Trial
Approval was based on improved progression-free survival in an international open-label trial in 322 patients with histologically confirmed stage IIIC or IV melanoma determined to be BRAF V600E or V600K mutation–positive based on centralized testing.3 Patients were randomized to receive either trametinib at 2 mg orally once daily (n = 214) or chemotherapy consisting of either IV dacarbazine at 1,000 mg/m2 or paclitaxel at 175 mg/m2 every 3 weeks (n = 108).
No more than one prior chemotherapy regimen was permitted, and patients with prior exposure to BRAF inhibitors or MEK inhibitors were excluded from the trial. Patients with abnormal left-ventricular ejection fraction, history of acute coronary syndrome within 6 months, or current evidence of class II or greater congestive heart failure were also excluded. Among all patients, median age was 54 years, 54% were male, all had ECOG performance status of 0 or 1, and 64% had M1c disease. All patients had tumor tissue with mutations in BRAF V600E (87%), V600K (12%), or both (< 1%). At the time of disease progression, 51 chemotherapy patients (47%) received trametinib.
Trametinib treatment was associated with a significant 53% reduction in risk of progression (median progression-free survival, 4.8 vs 1.5 months, hazard ratio = 0.47, P < .0001). Progression-free survival analysis based on blinded independent central review was consistent with the investigator results. Objective response rates were 22% in the trametinib group and 8% in the chemotherapy arm. Overall survival data are not yet mature.
In a separate single-arm trial in 40 patients with BRAF V600E or V600K mutation–positive unresectable or metastatic melanoma who had received prior treatment with a BRAF inhibitor, trametinib showed no evidence of antitumor activity (no confirmed partial or complete responses).
How It Works
Trametinib is a reversible inhibitor of MEK1 and MEK2 activation and MEK1 and MEK2 kinase activity. MEK proteins are upstream regulators of the ERK pathway, which promotes cellular proliferation. BRAF V600E mutations result in constitutive activation of the BRAF pathway, which includes MEK1 and MEK2. Trametinib inhibits BRAF V600 mutation–positive melanoma cell growth in vitro and in vivo.
How It Is Given
The recommended dose of trametinib is 2 mg orally once daily, at least 1 hour before or 2 hours after a meal, until disease progression or unacceptable toxicity.
Dose modification or discontinuation is required for cutaneous, cardiac (reduced left-ventricular ejection fraction, symptomatic congestive heart failure), ocular (retinal pigment epithelial detachment, retinal vein occlusion), and pulmonary (interstitial lung disease, pneumonitis) toxicities. Appropriate doses have not been established for patients with moderate to severe hepatic impairment or severe renal impairment.
The presence of BRAF V600E or V600K mutation in tumor specimens must be confirmed prior to initiation of trametinib treatment. Information on approved tests for the detection of BRAF V600 mutations in melanoma is available from the FDA.4
Safety Profile
The most frequent (≥ 20%) adverse events of any grade in the trametinib group were rash (57% vs 10% in the chemotherapy group), diarrhea (43% vs 16%), and lymphedema (32% vs 4%). The most frequent grade 3 or 4 adverse events in the trametinib group were hypertension (12%) and rash (8%). The most common laboratory abnormalities of any grade in trametinib patients were increased AST (60% vs 16%), hypoalbuminemia (42% vs 23%), increased ALT (39% vs 20%), and anemia (38% vs 26%); grade 3 adverse events in these categories occurred in 2% to 3% of trametinib patients.
Adverse events led to discontinuation of trametinib treatment in 9% of patients, with the most common reasons being decreased left-ventricular ejection fraction, pneumonitis, renal failure, diarrhea, and rash, and to dose reduction in 27% of patients, with the most common reasons being rash and reduced left-ventricular ejection fraction. Serious adverse events in trametinib recipients included cardiomyopathy, retinal pigment epithelial detachment, retinal vein occlusion, interstitial lung disease, and serious skin toxicity.
Trametinib carries warnings/precautions for cardiomyopathy, retinal pigment epithelial detachment, retinal vein occlusion, interstitial lung disease, serious skin toxicity, and embryo-fetal toxicity. Left-ventricular ejection fraction must be assessed prior to treatment and after 1 month and every 2 to 3 months thereafter. Ophthalmologic exams should be performed for any visual disturbance, and patients should be monitored for pulmonary symptoms and skin toxicities and secondary infections. Women should be advised on pregnancy planning and contraception, and men should be advised on potential impairment of fertility. Nursing mothers should discontinue trametinib or discontinue nursing. ■
Report Adverse Events
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
References
1. U.S. Food and Drug Administration: Trametinib. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm354478.htm. Accessed June 11, 2013.
2. MEKINISTTM (trametinib) tablets prescribing information, GlaxoSmithKline, May 2013. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2013/204114s000lbl.pdf
3. Flaherty KT, Robert C, Hersey P, et al: Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 367:107-114, 2012.
4. U.S. Food and Drug Administration: Medical devices: Companion diagnostic devices: In vitro and imaging tools. Available at http://www.fda.gov/CompanionDiagnostics. Accessed June 11, 2013.
