FDA Approval for Dabrafenib
Brand name(s): Tafinlar™
- Approved for unresectable or metastatic melanoma with BRAF V600E mutation
Full prescribing information is available, is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
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.
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 Division of Oncology Drug Products, or Patricia Keegan, M.D., director of the FDA's Division of Clinical Trials Design and Analysis.
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