FDA Approval Summary: Vemurafenib for Treatment of Unresectable or Metastatic Melanoma with the BRAF V600E Mutation.

Kim G1, McKee AE2, Ning YM2, Hazarika M3, Theoret M4, Johnson JR2, Xu QC5, Tang S6, Sridhara R7, Jiang X7, He K5, Roscoe D8, McGuinn WD2, Helms WS9, Russell AM10, Pope Miksinski S2, Fourie Zirkelbach J11, Earp J12, Liu Q13, Ibrahim A2, Justice R14, Pazdur R15.

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Abstract

On August 17, 2011, the FDA approved vemurafenib tablets (ZELBORAF, Hoffmann-LaRoche Inc.) for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an FDA-approved test. The cobas® 4800 BRAF V600 Mutation Test (Roche Molecular Systems, Inc.) was approved concurrently. An international, multicenter, randomized, open-label trial in 675 previously untreated patients with BRAF V600E mutation-positive unresectable or metastatic melanoma allocated 337 patients to receive vemurafenib 960 mg orally twice daily and 338 patients to receive dacarbazine 1000 mg/m2 intravenously every 3 weeks. Overall survival (OS) was significantly improved in patients receiving vemurafenib [hazard ratio (HR) 0.44; 95% CI, 0.33-0.59; p< 0.0001)]. Progression-free survival (PFS) was also significantly improved in patients receiving vemurafenib (HR 0.26; 95% CI, 0.20-0.33; p<0.0001). Overall response rates (ORR) were 48.4% and 5.5% in the vemurafenib and dacarbazine arms, respectively. The most common adverse reactions (≥30%) in patients treated with vemurafenib were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, and nausea. Cutaneous squamous cell carcinomas (cuSCC) or keratoacanthomas were detected in approximately 24% of patients treated with vemurafenib. Other adverse reactions included hypersensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, uveitis, QT prolongation, and liver enzyme laboratory abnormalities.