Dabrafenib for Unresectable or Metastatic Melanoma with BRAF V600E Mutation 

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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. 


On May 29, 2013, dabrafenib (Tafinlar) was approved for treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by a U.S. Food and Drug Administration (FDA)-approved test.1,2 Concurrent with this approval, FDA approved the THxID BRAF assay (bioMérieux, Inc) for detection of BRAF V600E mutations. Dabrafenib is not indicated for the treatment of patients with wild-type BRAF melanoma, due to the potential risk of tumor promotion.

Approval of dabrafenib was based on improved progression-free survival in an international, open-label trial in 250 patients with previously untreated, histologically confirmed, unresectable stage III or IV melanoma determined to be BRAF V600E mutation–positive based on centralized testing.2,3 Patients were randomized to receive either dabrafenib at 150 mg orally twice daily (n = 187) or dacarbazine at 1,000 mg/m2 IV once every 3 weeks (n = 63). At the time of disease progression, 28 dacarbazine patients received dabrafenib.

Overall, patients had a median age of 52 years, 60% were male, 67% had ECOG performance status of 0, and 66% had M1c disease. The trial excluded patients with abnormal left-ventricular ejection fraction or cardiac valve morphology (≥ grade 2), corrected QT interval ≥ 480 milliseconds on electrocardiogram, or a known history of glucose-6 phosphate dehydrogenase deficiency.

Dabrafenib significantly reduced investigator-assessed progression by 67% (median progression-free survival = 5.1 vs 2.7 months, hazard ratio = 0.33, P < .0001). A progression-free survival analysis based on blinded independent central review was consistent with the investigator results. Objective response rates were 52% in the dabrafenib group (including complete response in 3%) and 17% in the dacarbazine group. Median duration of response was approximately 5 months in both groups. There was no statistically significant difference in overall survival between the two groups.

How It Works

Dabrafenib is an inhibitor of some mutated forms of BRAF kinases. Some mutations in the BRAF gene, including those that result in the BRAF V600E enzyme, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth. Dabrafenib inhibits BRAF V600 mutation–positive melanoma cell growth in vitro and in vivo. Dabrafenib also inhibits wild-type BRAF and CRAF kinases (and other kinases, such as SIK1, NEK11, and LIMK1). However, in vitro experiments have shown paradoxical activation of MAP kinase signaling and increased cell proliferation in BRAF wild-type cells exposed to BRAF inhibitors.

How It Is Given

The recommended dose for dabrafenib is 150 mg orally twice 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 febrile drug reactions. No dose modifications are recommended for new primary cutaneous malignancies. Concurrent administration of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 (eg, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, St. John’s wort) is not recommended, and concomitant use of dabrafenib with agents that are sensitive substrates of CYP3A4, CYP2C8, CYP2C9, CYP2C19, or CYP2B6 (eg, midazolam, omeprazole, lansoprazole, rosiglitazone, warfarin) may result in loss of efficacy of these agents. Drugs that increase gastric pH (eg, proton pump inhibitors and H2-receptor blockers) may decrease dabrafenib concentrations. Appropriate doses have not been established for patients with moderate to severe hepatic impairment or severe renal impairment.

The presence of BRAF V600E mutation in tumor specimens must be confirmed prior to initiation of dabrafenib treatment. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at

Safety Profile

The most common (≥ 20%) adverse events of any grade in dabrafenib patients were hyperkeratosis (37% vs 0% with dacarbazine), headache (32% vs 8%), pyrexia (28% vs 10%), arthralgia (27% vs 2%), papilloma (27% vs 2%), alopecia (22% vs 2%), and palmar-plantar erythrodysesthesia syndrome (20% vs 2%). The most common grade 3 or 4 adverse events were cutaneous squamous cell carcinoma (4% vs 0%), pyrexia (3% vs 0%), and back pain (3% vs 0%).

Laboratory abnormalities more common in dabrafenib patients were hyperglycemia (50% vs 43%, grade 3 or 4 in 6% vs 0%), hypophosphatemia (37% vs 14%, grade 3 or 4 in 6% vs 2%), increased alkaline phosphatase (19% vs 14%, grade 3 or 4 in 0% vs 2%), and hyponatremia (8% vs 3%, grade 3 or 4 in 2% vs 0%). Adverse events resulted in permanent discontinuation of study medication in 3% of both groups. The most frequent adverse events leading to dabrafenib dose reduction were pyrexia (9%), palmar-plantar erythrodysesthesia syndrome (3%), chills (3%), fatigue (2%), and headache (2%).

Serious adverse events in dabrafenib patients consisted of 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 carries warnings/precautions for new primary cutaneous malignancies, tumor promotion in BRAF wild-type melanoma, serious febrile drug reactions, hyperglycemia, uveitis and iritis, glucose-6-phosphate dehydrogenase deficiency, and embryo-fetal toxicity. Patients should undergo dermatologic evaluation prior to treatment, every 2 months during treatment, and for up to 6 months after stopping treatment. Serum glucose levels should be monitored in patients with preexisting diabetes or hyperglycemia. Patients should be monitored routinely for visual symptoms.

Female patients should be advised to use highly effective contraception during treatment and for 4 weeks after stopping treatment and males should be advised of the potential risk for impaired spermatogenesis. Since dabrafenib may reduce the effectiveness of hormonal contraceptives, an alternative method of contraception should be used. Nursing mothers should discontinue dabrafenib treatment or discontinue nursing. ■


1. U.S. Food and Drug Administration: Dabrafenib. Available at Accessed June 11, 2013.

2. TAFINLAR® (dabrafenib) capsules prescribing information, GlaxoSmithKline, May 2013. Available at Accessed June 11, 2013.

3. Hauschild A, Grob JJ, Demidov LV, et al: Dabrafenib in BRAF-mutated metastatic melanoma. Lancet 380:358-365, 2012.