FDA approved Zelboraf (vemurafenib) for BRAF V600E Melanoma and Erdheim-Chester DiseaseFDA approved new drug Zelboraf for advanced melanoma with BRAF mutation

Zelboraf is a kinase inhibitor. The label states it is indicated for BRAF V600E mutation-positive melanoma and BRAF V600 mutation-positive Erdheim-Chester Disease, but does not provide a detailed mechanism of action.

Zelboraf is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. It is also indicated for the treatment of patients with Erdheim-Chester Disease with BRAF V600 mutation. Limitation of Use: Zelboraf is not indicated for treatment of patients with wild-type BRAF melanoma.

Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment for melanoma. The recommended dose is 960 mg (four 240 mg tablets) orally every 12 hours with or without a meal. A missed dose can be taken up to 4 hours prior to the next dose. Treat until disease progression or unacceptable toxicity. Do not take an additional dose if vomiting occurs; continue with the next scheduled dose. Do not crush or chew tablets. Dose modifications: For new primary cutaneous malignancies, no dose modifications are recommended. For other adverse reactions, permanently discontinue for Grade 4 adverse reaction, or first appearance (if clinically appropriate) or second appearance of QTc prolongation > 500 ms and increased by > 60 ms from pre-treatment values. Withhold for intolerable Grade 2 or greater adverse reactions; upon recovery to Grade 0-1, restart at reduced dose: 720 mg twice daily for first appearance of intolerable Grade 2 or Grade 3 adverse reactions; 480 mg twice daily for second appearance of Grade 2 (if intolerable) or Grade 3 adverse reactions or for first appearance of Grade 4 adverse reaction (if clinically appropriate). Do not dose reduce below 480 mg twice daily. For strong CYP3A4 inducers: avoid concomitant use; if unavoidable, increase dose by 240 mg (one tablet) as tolerated. After discontinuation of the inducer for two weeks, resume the prior dose.

Trial 1 was an international, open-label, randomized controlled trial in 675 treatment-naive patients with BRAF V600E mutation-positive unresectable or metastatic melanoma. Patients received Zelboraf 960 mg orally twice daily (n=337) or dacarbazine 1000 mg/m2 intravenously on Day 1 every 3 weeks (n=338). The major efficacy outcomes were overall survival (OS) and investigator-assessed progression-free survival (PFS). The trial demonstrated statistically significant increases in OS and PFS in the Zelboraf arm. Hazard ratio for OS was 0.47 (95% CI: 0.35, 0.62), p < 0.0001. Updated median OS was 13.6 months (95% CI: 12.0, 15.3) versus 10.3 months (95% CI: 9.1, 12.8). Hazard ratio for PFS was 0.26 (95% CI: 0.20, 0.33), p < 0.0001; median PFS was 5.3 months versus 1.6 months. Confirmed best overall response rate was 48.4% (95% CI: 41.6%, 55.2%) versus 5.5% (95% CI: 2.8%, 9.3%).

The label does not list specific contraindications. Warnings and precautions include: not for use in wild-type BRAF melanoma (see section 5.2), and QTc prolongation (see section 5.5). Dose modifications are required for adverse reactions and strong CYP3A4 inducers.

Zelboraf is a targeted therapy for