A Phase III multicenter clinical trial finds that treatment with the investigational BRAF-targeted drug dabrafenib, an investigational, orally bioavailable inhibitor of the BRAF protein, reduced the risk of disease progression by 70% compared to standard dacarbazine chemotherapy in patients with previously untreated, advanced melanoma with mutations in the BRAF gene. The results were presented at the 48th Annual Meeting of the American Society of Clinical Oncology (ASCO).

The investigators also noted that there appeared to be fewer cases of serious skin toxicities associated with dabrafenib treatment, including squamous cell carcinomas, than have been previously reported in other trials evaluating the current standard targeted drug for these patients, vemurafenib (Zelboraf?, Genentech).

Another advance in the treatment of melanoma
“For three decades, we had no new therapies for metastatic melanoma, but we?re quickly gaining momentum. Last year, ipilimumab (Yervoy?, Bristol-Myers Squibb) and vemurafenib were approved, and now dabrafenib could be on the horizon,” explained lead author and global principal investigator Axel Hauschild, MD, Professor of Dermatology at the University Hospital in Kiel, Germany. “These findings represent another advance for melanoma and form the foundation for further studies to evaluate the role of dabrafenib in combination with other drugs.?

Like vemurafenib, dabrafenib is taken orally and works by inhibiting BRAF, an altered protein that drives the growth of metastatic melanoma. Previous studies have suggested that patients taking vemurafenib have an increased risk of sun sensitivity and secondary, less serious skin tumors (such as squamous cell cancers); these occurred in 12% and 12% of patients, respectively, in a Phase III trial. However, patients taking dabrafenib in this study reported a low incidence of such serious skin side effects: 3% had photosensitivity and 6 percent developed squamous cell carcinomas.

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Trial results
In this study, called BREAK-3, patients with previously untreated, inoperable stage III or IV melanoma were randomly assigned to receive dabrafenib (187 patients) or standard chemotherapy, dacarbazine (63 patients). Fifty percent of patients in the dabrafenib group responded to therapy, compared with 6% of patients treated with dacarbazine (independent reviewer confirmed figures). Estimated median progression-free survival was significantly longer in the dabrafenib group: 5.1 months versus 2.7 months. Overall survival data are not yet mature, but may be difficult to assess since patients whose disease progressed on dacarbazine were permitted to cross over to the dabrafenib study arm.
Both treatments were generally well-tolerated. More patients in the dacarbazine group experienced drops on their blood cell counts, while more patients in the dabrafenib group experienced mild to moderate skin reactions, joint pain and fever.

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Presentation: Monday, June 4, 2012, 8:00 ? 8:15 AM CDT
Abstract: #LBA8500
Title: Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine (DTIC) in patients with BRAFV600E-mutated melanoma.
Authors: Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, et al.

Photo Credit: Chicago, IL – ASCO 2012 Annual Meeting: 96291/LBA8500. Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine (DTIC) in patients with BRAFV600E-mutated melanoma. A. Hauschild MD, Professor of Dermatology at the University Hospital in Kiel, Germany,.during the Oral Melanoma session at the American Society for Clinical Oncology (ASCO) Annual Meeting, Monday June 4, 2012. Over 31,000 physicians, researchers and healthcare professionals from over 100 countries are attending the meeting which is being held at the McCormick Convention center and features the latest cancer research in the areas of basic and clinical science. Photo by ? ASCO/Todd Buchanan 2012.

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