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Key clinical-trial evidence for dabrafenib

Author: Anoma Ranaweera, Medical Writer, Auckland, New Zealand, 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 characterised by high response rates, a rapid mode of action, little toxicity, and a prolonged progression-free survival (PFS) over chemotherapy.

BREAK-1 trial highlights

  • This phase I trial (BREAK-1) included 156 melanoma patients with BRAF mutations.
  • A recommended dose of dabrafenib 150mg twice daily was selected after dose titration.
  • The phase I study showed dabrafenib to be safe and tolerable, was active against BRAFV600E and BRAFV600K melanoma, and melanoma metastases in the brain.
  • The median PFS was similar (approximately 5.5 months) in BRAFV600E and BRAFV600K patients.
  • Nine (90%) of the ten patients with BRAFV600 melanoma and previously untreated brain metastases showed a decrease in the size of their brain tumours, with four patients (40%) achieving complete responses.
  • The most common grade 2 or higher toxicities were cutaneous squamous cell carcinoma (SCC) or keratoacanthoma (KA) (11%), fatigue (8%), and pyrexia (6%).
  • Palmoplantar hyperkeratoses and actinic keratoses were common (26% and 10%, respectively) but mild.
  • Dose reductions occurred in 7% of patients.
  • 76% of patients had no drug-related adverse events of greater severity than grade 2.

Key efficacy findings are summarised in the table below.

Clinical summary: BREAK-1 trial
No. of melanoma patients 156
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

  • This single-arm, open-label, phase II trial included 92 patients with BRAFV600E or BRAFV600K metastatic melanoma without prior therapy with BRAF or MEK inhibitors.
  • The primary objective was to determine the response rate in BRAFV600E patients, with secondary objectives including response rate in BRAFV600K patients, duration of response, progression free survival (PFS), overall survival (OS), safety, and tolerability.
  • Dabrafenib was dosed at 150 mg twice daily administered orally.
  • Response rates were impressive in BRAFV600E patients (7% complete response, 53% partial response) but less so in BRAFV600K patients (0% complete response, 13% partial response).
  • A minority of patients (16% BRAFV600E, 31% BRAFV600K) appeared to derive no benefit from treatment and had progressive disease at first assessment.
  • The median PFS was longer (27 weeks in BRAFV600E patients, 20 weeks in BRAFV600K patients) than that reported for standard chemotherapies.
  • Adverse events were common but rarely led to dose reduction (14%) or discontinuation (1%).
  • Most frequent (ranging from 15% to 33%) toxicities of any grade were arthralgia, hyperkeratosis, pyrexia, fatigue, headache, nausea, and skin papillomas.
  • Serious adverse events occurred in 27% of patients and included cutaneous sqamous cell carcinomas (9%), basal-cell carcinomas (4%), and pyrexia (3%).
Clinical summary: BREAK-2 trial
No. of melanoma patients 92
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

  • This phase III trial recruited 250 patients with stage IV or inoperable stage IIIC BRAFV600E melanoma, with no prior therapy for advanced disease (apart from interleukin-2 in one patient), and an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1.
  • The trial was conducted in a 3:1 randomized, open-label design, with patients receiving either dabrafenib 150 mg twice daily or dacarbazine (1000 mg/m2 every 3 weeks, IV), with crossover to dabrafenib upon disease progression in those receiving dacarbazine.
  • The primary end point was investigator-assessed progression-free survival (PFS).
  • Secondary end points included PFS, as assessed by an independent review committee (IRC); overall survival (OS); objective response rate by revised RECIST (Response Evaluation Criteria in Solid Tumours) guidelines (version 1.1), as determined by an investigator and an Independent Review Committee; PFS after crossover from dacarbazine to dabrafenib; duration of response; quality of life; safety; and tolerability.
  • 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-phosphate dehydrogenase deficiency.
  • The median duration on treatment was 4.9 months for patients treated with debrafenib and 2.8 months for dacarbazine-treated patients. The population exposed to dabrafenib was 60% male, 99% white, and had a median age of 53 years.
  • Toxicities were similar to those seen in the early-phase trials, the most common being cutaneous manifestations (hyperkeratosis, papillomas, palmar-plantar erythrodysesthesia), pyrexia, fatigue, headache, and arthralgia.
  • Dose reductions occurred in 28% of patients, and 3% of patients permanently discontinued therapy because of toxicity.
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

  • This phase II trial (BREAK-MB) included 172 BRAF mutation melanoma patients with at least one brain metastasis
  • There were two cohorts: those with newly diagnosed brain metastases (A) and those that had received previous local treatments (B).
  • Dabrafenib dose was 150 mg twice daily.
  • It was equally effective in both cohorts.
  • Side effects were similar to BREAK-1, 2 and 3 trials.
Clinical summary: BREAK-MB trial
No. of melanoma patients 172
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

Approved datasheets are the official source of information for medicines, including approved uses, doses, and safety information. Check the individual datasheet in your country for information about medicines.

We suggest you refer to your national drug approval agency such as the Australian Therapeutic Goods Administration (TGA), US Food and Drug Administration (FDA)UK Medicines and Healthcare products regulatory agency (MHRA) / emc, and NZ Medsafe, or a national or state-approved formulary eg, the New Zealand Formulary (NZF) and New Zealand Formulary for Children (NZFC) and the British National Formulary (BNF) and British National Formulary for Children (BNFC).



  • Falchook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 2012; 379: 1893–901. PubMed
  • Trefzer U, Minor DR, Ribas A, et al. BREAK-2: a phase IIA trial of the selective BRAF kinase inhibitor GSK2118436 in patients with BRAF (V600E/K)-positive metastatic melanoma [abstract]. Pigment Cell Melanoma Res 2011; 24: 1020. Abstract LBA1021–1021.
  • Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012; 380: 358–65. PubMed
  • Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 study. Lancet Oncol 2012; 13: 1087–95. PubMed

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