Key clinical-trial evidence for dabrafenib

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.

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%).

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.

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.

a: investigator-assessed intracranial response rate