Second European post-chicago melanoma meeting 2012.

Mutations of the serine/threonine-protein kinase BRAF protein are found in 80% of melanomas. Vemurafenib (Zelboraf, Genentech/Daiichi Sankyo), a specific inhibitor of BRAF, was approved by the FDA for metastatic melanoma in August 2011. Dabrafenib (GlaxoSmithKline, GSK 2118436), tested in the BREAK-2 trial, demonstrated a 59% confirmed response rate with a median progression-free survival (PFS) of 6.3 months. Like vemurafenib, it showed activity against V600E and V600K BRAF mutations.1 BREAK-3 was a phase 3 randomized, open-label study comparing dabrafenib (150 mg twice daily) with dacarbazine for injection (DTIC, Dome/Bayer) (1,000 mg/m2 intravenously every 3 weeks) in 250 previously untreated subjects with BRAFmutated, metastatic stage III/IV melanoma. The primary endpoint of investigator-assessed PFS was a median of 6.7 months for dabrafenib and 2.9 months for dacarbazine. The benefit, Dr. Grob commented, was similar to that found for vemurafenib when compared with dacarbazine. The PFS hazard ratios (HRs) for dabrafenib ranged from 0.23 to 0.38 for Eastern Cooperative Oncology Group (ECOG) status, lactate dehydrogenase (LDH) level, age, sex, and disease stage subgroups. Adverse effects were similar to those with vemurafenib, but pyrexia was more common and hyperkeratosis and photosensitivity were less common (3%). Dose modifications (3%), reductions (18%), and interruptions or delays (27%) were needed at identical rates for dabrafenib and dacarbazine. In a phase 2 study (BREAK–MB) among treatment-naive patients (n = 172) with BRAF V600E/V600K brain metastases receiving dabrafenib 150 mg twice daily, disease control (defined as complete response + partial response + stable disease) was achieved in similar proportions of patients with and without prior brain treatment (81%/89%, respectively, for V600E and 33%/50%, respectively, for V600K). In the V600E group, PFS was roughly 16 months and median overall survival was about 32 months, with or without prior brain treatment. Results in the V600K groups were also positive but less dramatic than in the V600E subjects. “These unprecedented response rates and survival may completely change our approach to brain metastases in BRAFmutated patients,” Dr. Grob said. A further study of dabrafenib in melanoma (phase 1/2), in combination with the oral MEK1 and MEK2 (MAP kinase kinase) inhibitor trametinib (GlaxoSmithKline, GSK 1120212), revealed a highly encouraging PFS of 10.8 months for patients receiving dabrafenib/trametinib (150 mg twice daily/2 mg once daily). The clinical activity with the combination, Dr. Grob said, was clearly better than with the MEK inhibitor alone. “Dabrafenib is a real competitor for vemurafenib with a slightly different toxicity profile,” he concluded.