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FDA Approval for Dabrafenib

Brand name(s): Tafinlar™

Full prescribing information is available, is available, including clinical trial information, safety, dosing, drug-drug interactions, and contraindications.

Approved for use with trametinib for unresectable or metastatic melanoma with BRAF V600E or BRAF V600K mutations

On January 10, 2014, the Food and Drug Administration granted accelerated approval to trametinib (Mekinist tablets, GlaxoSmithKline, LLC) and dabrafenib (Tafinlar capsules, GlaxoSmithKline, LLC) for use in combination to treat patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation as detected by an FDA-approved test.

Trametinib was previously approved in 2013 as a single agent for treatment of BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma. Dabrafenib was also approved in 2013 as a single agent for treatment of BRAF V600E mutation-positive unresectable or metastatic melanoma. Trametinib and dabrafenib target two different tyrosine kinases in the RAS/RAF/MEK/ERK pathway.

Approval of the combination therapy was based on the demonstration of durable objective responses in a multicenter open-label randomized active-controlled dose-ranging clinical trial that enrolled 162 patients with histologically confirmed stage IIIC or IV melanoma that was determined to have a BRAF V600E or V600K mutation. No more than one prior chemotherapy regimen and/or interleukin-2 were permitted. Patients with prior exposure to BRAF inhibitors or MEK inhibitors were ineligible.

Patients were randomly assigned to receive one of three treatment regimens:

  • trametinib 2 mg orally once daily in combination with dabrafenib 150 mg orally twice daily (n=54),
  • trametinib 1 mg orally once daily in combination with dabrafenib 150 mg orally twice daily (n=54), or
  • single-agent dabrafenib 150 mg orally twice daily (n=54). 

Of the 162 patients enrolled, 57 percent were male, and the median age was 53 years. All patients had a baseline ECOG performance status of 0 or 1, 67 percent had M1c disease, and 81 percent had not received prior anticancer therapy for unresectable or metastatic disease. All patients had tumor tissue with mutations in BRAF V600E (85 percent) or V600K (15 percent) on local or centralized testing.

The investigator-assessed objective response rates and response durations were 76 percent (95 percent CI: 62, 87) and 10.5 months (95 percent CI: 7, 15), respectively, in the trametinib 2 mg plus dabrafenib combination arm and 54 percent (95 percent CI: 40, 67) and 5.6 months (95 percent CI: 5, 7), respectively, in the single-agent dabrafenib arm. Objective response rates were similar in subgroups defined by BRAF V600 mutation subtype, V600E and V600K. Analyses of objective response rates based on blinded independent central review were consistent with the investigator results.

The incidence of cutaneous squamous cell carcinoma (including squamous cell carcinomas of the skin and keratoacanthomas), the trial’s primary safety endpoint, was 7 percent (95 percent CI: 2, 18) in the trametinib 2 mg plus dabrafenib combination arm compared with 19percent (95 percent CI: 9, 32) in the single-agent dabrafenib arm.

The most frequent (at least 20 percent incidence) adverse reactions from trametinib in combination with dabrafenib were fever, chills, fatigue, rash, nausea, vomiting, diarrhea, abdominal pain, peripheral edema, cough, headache, arthralgia, night sweats, decreased appetite, constipation, and myalgia. The most frequent grades 3 and 4 adverse events (at least 5 percent incidence) were acute renal failure, fever, hemorrhage, and back pain.

Serious adverse drug reactions occurring in patients taking trametinib in combination with dabrafenib were hemorrhage, venous thromboembolism, new primary malignancy, serious febrile reactions, cardiomyopathy, serious skin toxicity, and eye disorders such as retinal pigmented epithelial detachments.

Granting of this accelerated approval is contingent on the successful completion of the ongoing MEK115306 trial to verify the clinical benefit of trametinib for use in combination with dabrafenib. MEK115306 is an international multicenter randomized double-blind placebo-controlled trial that is comparing the combination of dabrafenib and trametinib with dabrafenib and placebo as first-line therapy in approximately 340 patients with unresectable (stage IIIC) or metastatic (stage IV) BRAF V600E or V600K mutation-positive cutaneous melanoma. The primary endpoint is progression-free survival. Overall survival is a key secondary endpoint.

The recommended dose and schedule for trametinib and dabrafenib when used in combination is trametinib 2 mg orally once daily with dabrafenib 150 mg orally twice daily, continued until disease progression or unacceptable toxicity occurs. Trametinib and dabrafenib should be taken at least one hour before or two hours after a meal. The once-daily dose of trametinib can be taken at the same time as either dose of dabrafenib

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Approved for unresectable or metastatic melanoma with BRAF V600E mutation

On May 29, 2013, the Food and Drug Administration (FDA) approved dabrafenib (Tafinlar™ capsule, made by GlaxoSmithKline, LLC), for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. Dabrafenib is not indicated for the treatment of patients with wild-type BRAF melanoma because of the potential risk of tumor promotion. Concurrent with this action, FDA approved the THxID BRAF assay (bioMerieux, Inc.) for detection of BRAFV600E mutations.

The approval of dabrafenib was based on demonstration of improved progression-free survival (PFS) in a multi-center international open-label randomized (3:1), active-controlled trial. This trial enrolled 250 patients with previously untreated, histologically confirmed, unresectable stage III or stage IV melanoma determined to be BRAFV600E mutation-positive based on centralized testing. Patients were randomly assigned to receive either dabrafenib 150 mg orally twice daily (n=187) or dacarbazine 1000 mg/m2 intravenously once every 3 weeks (n=63). At the time of disease progression, 28 patients who had been randomly assigned to receive dacarbazine received dabrafenib.

Of the 250 patients enrolled in the trial, 60 percent were male, the median age was 52 years, 67 percent had an ECOG performance status of 0, and 66 percent had M1c disease.

A statistically significant prolongation of investigator-assessed PFS was demonstrated for patients randomly assigned to receive dabrafenibcompared with those randomly assigned to receive dacarbazine[RC1]  [HR 0.33 (95 percent CI: 0.20, 0.54); p < 0.0001, stratified log-rank test]. The median PFS times were 5.1 months for patients treated with dabrafenib and 2.7 months for patients treated with dacarbazine. A PFS analysis that was based on blinded independent central review was consistent with the investigator results.

The investigator-assessed objective response rates were 52 percent (95 percent CI: 45, 59) for patients treated with dabrafenib, which included a 3 percent complete response rate, and 17 percent (95 percent CI: 9, 29) for patients treated with dacarbazine. The median duration of response was approximately 5 months in both treatment groups. No statistically significant difference in overall survival between the two treatment groups was demonstrated.

The most frequent (at least 20 percent incidence) adverse reactions from dabrafenib were hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome.

Serious adverse reactions were the development of new primary skin cancers (cutaneous squamous cell carcinoma, new primary melanomas, and keratoacanthomas), febrile drug reactions requiring hospitalization, hyperglycemia, and uveitis/iritis. Dabrafenib is approved with a Medication Guide to inform patients of these serious potential risks.

The recommended dose and schedule for dabrafenib is 150 mg orally twice daily until disease progression or unacceptable toxicity. Dabrafenib should be taken at least one hour before or two hours after a meal. Confirmation of the presence of BRAFV600E is needed prior to initiation of dabrafenib because of the risks of potential risk of tumor promotion in patients with BRAF wild-type melanoma.

This summary was provided by Richard Pazdur, M.D., director of the FDA's Office of Hematology and Oncology Products, or Patricia Keegan, M.D., director of the FDA's Division of Oncology Products 2.

The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.

 

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  • Updated: January 16, 2014