A costly revolution for a subgroup of patients with metastatic melanoma

Abstract

Summary ORIGINAL ARTICLE: 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. Background Dabrafenib, an inhibitor of mutated BRAF, has clinical activity with a manageable safety profile in phase I and II studies in patients with BRAF (V600)‐mutated metastatic melanoma. Hauschild et al. aimed to assess the efficacy of dabrafenib in a phase III trial of patients with BRAF (V600)‐mutated metastatic melanoma. Methods Patients were enrolled into a phase III trial between December 2010 and September 2011. This report is based on the cut‐off date of 19 December 2011. Patients with previously untreated stage IV or unresectable stage III BRAF (V600)‐mutated melanoma were randomly assigned (3:1) to receive dabrafenib (150 mg twice daily, orally) or dacarbazine (1000 mg m−2 intravenously every 3 weeks). Patients were stratified according to American Joint Committee on Cancer stage. The primary endpoint was investigator‐assessed progression‐free survival (PFS) and was analysed by intention to treat. Safety was assessed per protocol. Findings Of the 733 patients screened, 250 were randomly assigned to receive either dabrafenib (187 patients) or dacarbazine (63 patients). Median PFS was 5·1 months for dabrafenib and 2·7 months for dacarbazine, with a hazard ratio of 0·30 (95% confidence interval 0·18–0·51, P < 0·0001). At cut‐off, 107 (57%) patients in the dabrafenib group and 14 (22%) in the dacarbazine group remained on randomized treatment. Treatment‐related adverse events (grade 2 or higher) occurred in 100 (53%) of the 187 patients who received dabrafenib and in 26 (44%) of the 59 patients who received dacarbazine. The most common adverse events with dabrafenib were skin‐related toxic effects, fever, fatigue, arthralgia and headache. The most common adverse events with dacarbazine were nausea, vomiting, neutropenia, fatigue and asthenia. Grade 3–4 adverse effects were uncommon in both groups. Interpretation Dabrafenib significantly improved PFS compared with dacarbazine.

Antitumor effect of pharmacologic ascorbate in the B16 murine melanoma model

“…Treatment of these patients with BRAF inhibitors has improved progression-free and/or overall survival compared to treatment with the standard DNA alkylating chemotherapeutic, dacarbazine [4][5][6]. These treatments are indicated for a relatively small percentage of individuals, namely those with advanced melanoma and a BRAF V600 mutation [7]. Unfortunately, BRAF inhibitors have toxicities.…”

Concerns regardingBRAFtesting algorithm

“…Furthermore, the theoretical risk of primary tumours developing resistance to BRAF inhibitors prior to the development of stage III or IV disease has yet to be thoroughly explored. There is now evidence to suggest that administering BRAF inhibitors to patients with BRAF wild‐type metastases activates the mitogen‐activated kinase pathway in the these tumours, and accelerates growth and disease progression . Therefore, a false positive misdiagnosis could prove costly to the patient in terms of reduced survival, and costly to the treating hospital in terms of potential litigation.…”