The European Medicines Agency review of vemurafenib (Zelboraf®) for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma: summary of the scientific assessment of the Committee for Medicinal Products for Huma

The applicant company Roche Registration Ltd. submitted to the European Medicines Agency (EMA) an application for marketing authorisation for vemurafenib. Vemurafenib is a low molecular weight, orally available, inhibitor of oncogenic V600 BRAF serine-threonine kinase. Mutations in the BRAF gene which substitute the valine at amino acid position 600 constitutively activate BRAF proteins, which will drive cell proliferation in the absence of growth factors. Results from a phase 3 trial (N=675) comparing vemurafenib 960 mg twice daily (taken either with or without food) to standard treatment dacarbazine (DTIC) in patients with BRAF V600E mutation-positive unresectable or metastatic melanoma were submitted. The study met its primary efficacy objective after an interim analysis of overall survival. Patients were allowed to cross-over to the experimental arm following disclosure of the study results after the first interim analysis. In the update of the analysis, the median overall survival (OS) was 9.9 months versus 13.2 months for DTIC and vemurafenib, respectively (HR=0.67; 95% confidence interval (CI): 0.54, 0.84; cut-off 3 October 2011). Based on the updated analysis, the CHMP concluded that a survival benefit over DTIC had been convincingly demonstrated, in the overall population. The follow-up was considered sufficiently mature with close to 50% of the events observed. The most common side effects (affecting more than 30% of patients) in vemurafenib treated patients included arthralgia, fatigue, rash, photosensitivity reaction, nausea, alopecia and pruritus. Some patients treated with vemurafenib developed cutaneous squamous cell carcinoma which was readily treated by local surgery. The objective of this paper is to summarise the scientific review of the application leading to regulatory approval in the European Union (EU). The full scientific assessment report and product information, including the Summary of Product Characteristics (SmPC), are available on the EMA website (www.ema.europa.eu).

da Rocha Dias S ，Salmonson T ，van Zwieten-Boot B ，Jonsson B ，Marchetti S ，Schellens JH ，Giuliani R ，Pignatti F ... -  《-》

FDA approval summary: vemurafenib for treatment of unresectable or metastatic melanoma with the BRAFV600E mutation.

On August 17, 2011, the U.S. Food and Drug Administration (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, 1,000 mg/m(2) intravenously every 3 weeks. Overall survival was significantly improved in patients receiving vemurafenib [HR, 0.44; 95% confidence interval (CI), 0.33-0.59; P < 0.0001]. Progression-free survival was also significantly improved in patients receiving vemurafenib (HR, 0.26; 95% CI, 0.20-0.33; P < 0.0001). Overall response rates 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 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.

Kim G ，McKee AE ，Ning YM ，Hazarika M ，Theoret M ，Johnson JR ，Xu QC ，Tang S ，Sridhara R ，Jiang X ，He K ，Roscoe D ，McGuinn WD ，Helms WS ，Russell AM ，Miksinski SP ，Zirkelbach JF ，Earp J ，Liu Q ，Ibrahim A ，Justice R ，Pazdur R ... -  《-》

Vemurafenib in patients with BRAF V600E mutation-positive advanced melanoma.

Vemurafenib is an oral, small-molecule kinase inhibitor that selectively targets activated BRAF V600E and has been approved for the treatment of advanced BRAF mutation-positive melanoma. This article reviews the clinical pharmacology, efficacy, tolerability, and pharmacokinetics of vemurafenib and in addition outlines proposed mechanisms of vemurafenib resistance. A literature search of MEDLINE and ScienceVerse Scopus was performed using the key words malignant melanoma, BRAF, vemurafenib, and PLX4032. Scientific abstracts, US Food and Drug Administration Web site data (www.accessdata.fda.gov), the manufacturer-submitted approval data from ClinicalTrials.gov (www.clinicaltrials.gov), and the references from applicable publications were also consulted. Clinical studies have reported that vemurafenib is efficacious and acceptably well-tolerated. In a Phase I study (BRIM-1), a 960-mg BID dose achieved an objective response rate of 81% among 32 patients with melanoma who carried a BRAF V600E mutation. Of the 26 responders, 2 achieved a complete response and 24 a partial response. In BRIM-2, 132 BRAF V600E-positive patients achieved an overall response rate of 53% (95% CI, 44%-62%); 6% achieved a complete response and 47%, a partial response. Response was noted at 6 weeks and lasted a median of 6.7 months (95% CI, 5.6-8.6). Median survival was 15.9 months (95% CI, 11.6-18.3); 77% of patients survived to 6 months (95% CI, 70-85) and 58% to 12 months (95% CI, 11.6-18.3), and an estimated 43% were expected to survive to 18 months (95% CI, 33-53). The Phase III study (BRIM-3) compared vemurafenib to dacarbazine. The hazard ratio (HR) for death with vemurafenib was 0.37 (95% CI, 0.26-0.55; P < 0.001). At 6 months, overall survival was 84% (95% CI, 78-89) versus 64% (95% CI, 56-73) in the vemurafenib and dacarbazine treatment arms, respectively. The HR for tumor progression in the vemurafenib cohort was 0.26 (95% CI, 0.20-0.33; P < 0.001), and the estimated median progression-free survival was 5.3 months with vemurafenib versus 1.6 months with dacarbazine. Finally, the difference in response rates was significant (48% vs 5%, respectively; P < 0.001). The most common adverse events reported have been arthralgia, rash, photosensitivity, fatigue, pruritus, alopecia, cutaneous squamous cell carcinoma, diarrhea, and mild to moderate nausea. Vemurafenib is effective for advanced melanomas expressing the BRAF V600E mutations. Resistance to BRAF inhibition can be problematic, but new evidence suggests that combination therapy may attenuate the issue. Targeting the cellular activity of melanoma cells is reported to be efficacious and is expected to delay progression and prolong survival.

Ravnan MC ，Matalka MS 《-》

Vemurafenib in patients with BRAF(V600) mutated metastatic melanoma: an open-label, multicentre, safety study.

The orally available BRAF kinase inhibitor vemurafenib, compared with dacarbazine, shows improved response rates, progression-free survival (PFS), and overall survival in patients with metastatic melanoma that has a BRAF(V600) mutation. We assessed vemurafenib in patients with advanced metastatic melanoma with BRAF(V600) mutations who had few treatment options. In an open-label, multicentre study, patients with untreated or previously treated melanoma and a BRAF(V600) mutation received oral vemurafenib 960 mg twice a day. The primary endpoint was safety. All analyses were done on the safety population, which included all patients who received at least one dose of vemurafenib. This report is the third interim analysis of this study. This study is registered with ClinicalTrials.gov, number NCT01307397. Between March 1, 2011, and Jan 31, 2013, 3226 patients were enrolled in 44 countries. 3222 patients received at least one dose of vemurafenib (safety population). At data cutoff, 868 (27%) patients were on study treatment and 2354 (73%) had withdrawn, mainly because of disease progression. Common adverse events of all grades included rash (1592 [49%]), arthralgia (1259 [39%]), fatigue (1093 [34%]), photosensitivity reaction (994 [31%]), alopecia (826 [26%]), and nausea (628 [19%]). 1480 (46%) patients reported grade 3 or 4 adverse events, including cutaneous squamous cell carcinoma (389 [12%]), rash (155 [5%]), liver function abnormalities (165 [5%]), arthralgia (106 [3%]), and fatigue (93 [3%]). Grade 3 and 4 adverse events were reported more frequently in patients aged 75 years and older (n=257; 152 [59%, 95% CI 53-65] and ten [4%, 2-7], respectively) than in those younger than 75 years (n=2965; 1286 [43%, 42-45] and 82 [3%, 2-3], respectively). Vemurafenib safety in this diverse population of patients with BRAF(V600) mutated metastatic melanoma, who are more representative of routine clinical practice, was consistent with the safety profile shown in the pivotal trials of this drug. F Hoffmann-La Roche.

Larkin J ，Del Vecchio M ，Ascierto PA ，Krajsova I ，Schachter J ，Neyns B ，Espinosa E ，Garbe C ，Sileni VC ，Gogas H ，Miller WH Jr ，Mandalà M ，Hospers GA ，Arance A ，Queirolo P ，Hauschild A ，Brown MP ，Mitchell L ，Veronese L ，Blank CU ... -  《-》

Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib.

Sosman JA ，Kim KB ，Schuchter L ，Gonzalez R ，Pavlick AC ，Weber JS ，McArthur GA ，Hutson TE ，Moschos SJ ，Flaherty KT ，Hersey P ，Kefford R ，Lawrence D ，Puzanov I ，Lewis KD ，Amaravadi RK ，Chmielowski B ，Lawrence HJ ，Shyr Y ，Ye F ，Li J ，Nolop KB ，Lee RJ ，Joe AK ，Ribas A ... -  《-》