Key clinical-trial evidence for dabrafenib

Author: Anoma Ranaweera B.V. Sc; PhD (Clinical Biochemistry, University of Liverpool, UK), 2013.

What is dabrafenib?

Dabrafenib is an orally bioavailable inhibitor of mutant BRAF protein in patients with melanoma.

On May 29, 2013, the U. S. Food and Drug Administration (FDA) approved dabrafenib (TAFINLAR™ capsule, GlaxoSmithKline, LLC), for the treatment of patients with non-operable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. Concurrent with this action, FDA approved the THxID BRAF assay (bioMerieux, Inc.) for detection of BRAF V600E.

The company has also filed a Marketing Authorisation Application with the European Medicines Agency (EMA) for dabrafenib for treating adult melanoma patients with the same mutation. This regulatory application is currently under review (June 2013).

Dabrafenib is a selective BRAF inhibitor characterized by high response rates, a rapid mode of action, little toxicity, and a prolonged progression-free survival (PFS) over chemotherapy.

BREAK-1 trial highlights

Key efficacy findings are summarised in the table below.

Clinical summary: BREAK-1 trial
No. of melanoma patients156
No. BRAFV600E positive 131
No. BRAFV600K positive 18
No. With non-V600 BRAFmut 4
Response rate (% patients) 56 (V600E); 22 (V600K); 0 (other)
Progression free survival (months) 5.5 (each for V600E and V600K mutations)
Cutaneous SCC/KA 11% patients
Pyrexia 4% patients

BREAK-2 trial highlights

Clinical summary: BREAK-2 trial
No. of melanoma patients92
No. BRAFV600E positive 76
No. BRAFV600K positive 16
No. with non-V600 BRAFmut 0
Response rate (% patients) 60 (V600E); 13 (V600K)
Progression free survival (months) 6.2 (V600E); 4.6 (V600K)
Cutaneous SCC/KA 9% patients
Pyrexia 3% patients

BREAK-3 trial

Clinical summary: BREAK-3 trial
Dabrafenib (n = 187)Dacarbazine (n = 63)
Confirmed tumour responses    
Objective response rate 52% (95% CI 44, 59) 17% (95% CI 9, 29)
Complete response 6 patients (3%) 0
Partial response 91 patients (48%) 11 (17%)
Median duration of response 5.6 months Not reached
Progression free survival (PFS) [investigator assessed]    
Median, months (95% CI) 5.1 (4.9, 6.9) 2.7 (1.5, 3.2) [HR 0.3; p >0.0001]
IRC assessed PFS, median, months 6.7 2.9 (HR 0.35; 95% CI 0.2, 0.61)
Overall survival (months) Not available Not available
Toxicity (%)    
Cutaneous SCC/KA (all grades) 7 0
Pyrexia (grade 3) 3 0

BREAK-MB (brain metastasis) trial highlights

Clinical summary: BREAK-MB trial
No. of melanoma patients172
No. in cohort A 89
No. BRAFV600E positive 139
No. BRAFV600K positive 33
No. with non-V600 BRAFmut 0
Response rate (% patients) 31–36 (V600E); 7–22 (V600K)a
Overall Survival (months) 7.1–7.6 (V600E); 3.7–5.1 (V600K)
Progression free survival (months) 3.7 (V600E); 1.8–3.7 (V600K)
Cutaneous SCC/KA 5% patients
Pyrexia (grade 3) 6% patients

a: investigator-assessed intracranial response rate

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