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U.S. Department of Health and Human Services

Drugs

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Dabrafenib

On May 29, 2013, the U. S. Food and Drug Administration (FDA) approved dabrafenib (TAFINLAR capsule, GlaxoSmithKline, LLC), for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E 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 BRAF V600E 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 BRAF V600E mutation-positive based upon centralized testing.  Patients were randomized 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 randomized to dacarbazine received dabrafenib.
 
Of 250 patients enrolled, 60% were male; the median age was 52 years, 67% had an ECOG performance status of 0, and 66% had M1c disease.
 
A statistically significant prolongation of investigator-assessed PFS was demonstrated for patients randomized to the dabrafenib arm [HR 0.33 (95% CI: 0.20, 0.54); p < 0.0001, stratified log-rank test].  The median PFS times were 5.1 and 2.7 months in the dabrafenib and dacarbazine arms, respectively.  The PFS analysis based on blinded independent central review was consistent with the investigator results.
 
The investigator-assessed objective response rates were 52% (95% CI: 45, 59) for the dabrafenib arm, which included a 3% complete response rate, and 17% (95% CI: 9, 29) for the dacarbazine arm.  The median duration of response was approximately 5 months in both treatment arms.  No statistically significant difference in overall survival between the two arms was demonstrated.
 
The most frequent (≥20% incidence) adverse reactions from dabrafenib were hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome.
 
Serious adverse reactions were 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 BRAF V600E is needed prior to initiation of dabrafenib because of the risks of potential risk of tumor promotion in patients with BRAF wild-type melanoma.
 
Full prescribing information is available at:  http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202806s000lbl.pdf
 
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and 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) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).