An agent that targets a genetic mutation active in half of melanoma cases substantially and safely shrank metastatic tumors. The drug, dabrafenib, also showed the most activity of any systemic treatment to date against secondary melanoma tumors in the brain.
Results of a phase 1 trial, recently published by The Lancet, illustrated the effectiveness of dabrafenib, which is an inhibitor of the BRAF oncogene. Approximately 50% of persons with metastatic melanoma have a BRAF mutation in their tumor, and the alteration also occurs in many other common cancer types including thyroid, colorectal, ovarian, and lung cancers. The most common BRAF mutations are Val600GIu and Val600Lys.
The study focused on 184 persons with incurable solid tumors, from eight centers in the United States and Australia. Most (156) of the participants had metastatic melanoma. During the course of the study, Gerald S. Falchook, MD, of the University of Texas M. D. Anderson Cancer Center in Houston, and coinvestigators established a recommended dose of 150 mg of dabrafenib twice daily, which was administered to three groups of patients with BRAF-mutant tumors: those with advanced melanoma, those with untreated melanoma brain metastases, and those with other BRAF-mutant solid tumors.
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“Brain metastases in most [nine out of 10] patients given dabrafenib reduced in size, with four patients’ metastases completely resolving,” Falchook summarized in a statement issued by The Lancet.
Although persons with melanoma and brain metastases typically survive for less than 5 months, “In this study, all 10 patients were alive at this stage, and two patients had durable antitumor activity with survival beyond 12 months,” pointed out Falchook, adding that one patient remains on treatment at 19 months.
Of the 36 patients with Val600 BRAF-mutant melanoma, 18 (50%) had confirmed responses to treatment. Responses were durable, with 17 patients (47%) on treatment for more than 6 months.
Among the 28 patients with BRAF-mutant solid tumors other than melanoma, apparent antitumor activity was noted in a gastrointestinal stromal tumor, papillary thyroid cancer, non-small-cell lung cancer, ovarian cancer, and colorectal cancer.
Most of the 184 patients (140, or 76%) had no treatment-related adverse events worse than grade 2. The most common treatment-related adverse events of grade 2 or worse were cutaneous squamous-cell carcinoma in 11% (20 patients), fatigue in 8% (14 patients), and pyrexia in 6% (11 patients). No deaths or discontinuations resulted from the adverse events, although 13 patients (7%) needed dose reductions.
