BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)
Early phase trials
Dabrafenib (Tafinlar ®, GSK2118436, GlaxoSmithKline, London) is a selective BRAF inhibitor developed after vemurafenib. A phase I/II study of dabrafenib was conducted in Australia and the United States between May 2009 and March of 2011 . The phase I component initially permitted entry regardless of BRAF mutation status but subsequently restricted enrollment to BRAFV600E or BRAFV600K mutant melanoma after several patients lacking BRAF mutations failed to respond. In contrast to the vemurafenib trials, patients with BRAFV600K mutant melanoma were allowed to enroll, including nine patients in this study. While dose-limiting toxicity was not found, the phase II recommended dose (RP2D) was determined to be 150 mg twice daily; 46 patients received this dose. Disease characteristics were unfavorable including 91% with AJCC stage M1c melanoma and 22% with brain metastases (see “Special Clinical Situations” below). Of the 36 patients with only extracranial metastases treated with the RP2D, 69% experienced partial or complete responses (50% confirmed) with median PFS of 5.5 months. Elevated LDH and worse baseline performance status predicted for more rapid disease progression. Cutaneous squamous cell carcinomas developed in 11% of patients who received at least 50 mg twice daily. Additional cutaneous toxicities were similar to vemurafenib, although photosensitivity was not observed. The most prevalent distinct non-cutaneous toxicity was pyrexia (20%, grade 3–4 in 4%).
Phase III clinical trial
This encouraging clinical activity led to the initiation of a multicenter, phase III trial of dabrafenib compared to cytotoxic chemotherapy . Two-hundred fifty patients were randomized 3:1 to dabrafenib 150 mg twice daily or dacarbazine; enrollment in this trial was limited to BRAFV600E mutant melanoma and to patients without brain metastases. The primary endpoint was PFS; crossover was allowed from dacarbazine to dabrafenib at disease progression. Baseline characteristics included 67% with ECOG performance status of 0, 65% with AJCC stage IVc disease, 34% with elevated LDH, and 98% with any previous therapy. Median PFS was 5.1 months with dabrafenib compared to 2.7 months with dacarbazine (hazard ratio for progression 0.30, 95% CI 0.18–0.51; p<0.0001). An independent review determined median PFS durations of 6.7 months and 2.9 months for dabrafenib and dacarbazine, respectively. This trial was not powered for overall survival, although a trend to improved OS with dabrafenib was observed (hazard ratio 0.61, 95% CI 0.25–1.48). Confirmed objective responses were seen in 53% of patients on dabrafenib (3% CR). As with vemurafenib, the vast majority of patients had some degree of tumor shrinkage with primary disease progression occurring only rarely. Adverse events were similar and included cSCCs/keratocanthomas (6%) and 11% with pyrexia (3% with= grade 3). Arthralgias, asthenia, headaches, and fatigue also occurred in > 5% of patients but were rarely severe. Notably, two patients developed second primary melanomas and four developed basal cell carcinomas. Dabrafenib received regulatory approval in the United States in May of 2013.
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