Manufacturer:

Genentech, Inc.

Pharmacological Class:

Kinase inhibitor.

Active Ingredient(s):

Vemurafenib 240mg; tabs.

Indication(s):

Treatment of unresectable or metastatic melanoma with BRAF^V600E mutation as detected by an FDA-approved test.

Pharmacology:

Vemurafenib is a low molecular weight inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAF^V600E. Vem­urafenib also inhibits other kinases in vitro such as CRAF, ARAF, wild-type BRAF, SRMS, ACK1, MAP4K5 and FGR at similar concentrations. Some mutations in the BRAF gene including V600E result in constitutively activated BRAF proteins, which can cause cell proliferation in the absence of growth factors that would normally be required for proliferation. Vemurafenib has anti-tumor effects in cellular and animal models of melanomas with mutated BRAF^V600E.

Clinical Trials:

The efficacy and safety of vemurafenib in patients with treatment naive, BRAF^V600E mutation-positive unresectable or metastatic melanoma as detected by the cobas 4800 BRAF V600 Mutation Test were assessed in an international, randomized trial. This trial involved 675 patients who were given either vemurafenib 960mg by mouth twice daily or dacarbazine 1000mg/m² IV on Day 1 every 3 weeks. The major efficacy outcome measures were overall survival (OS) and investigator-assessed progression-free survival (PFS). Other outcome measures included confirmed investigator-assessed best overall response rate. The median survival of patients who received vemurafenib has not been reached (77% still living) while the median survival for those who received dacarbazine was 7.9 months (64% still living). The median PFS for vemurafenib was 5.3 months compared to 1.6 months for dacarbazine. The overall response rate in the vemurafenib arm was 48.4% (95% CI: 41.6%, 55.2%) compared to 5.5% (95% CI: 2.8%, 9.3%) in the dacarbazine arm.

Legal Classification:

Rx

Adults:

Swallow whole with water. Take in the AM and PM (approx. 12 hours apart). ≥18 years: 960mg twice daily; until disease progression or unac­ceptable toxicity occurs. Dose modifications for adverse reactions or QTc prolongation: see literature. Dose reductions <480mg twice daily: not recommended.

Children:

<18 years: not recommended.

Warnings/Precautions:

Not for use in wild-type BRAF melanoma. Confirm BRAF^V600E mutation-positive melanoma with FDA-approved test before treating. Risk of cutaneous squamous cell carcinoma (cuSCC): ≥65 years, prior skin cancer, chronic sun exposure; if occurs, do excision and continue without dose adjustment. Do dermatologic evaluation before therapy, every 2 months during, and consider monitoring 6 months after. Long QT syndrome or QTc >500ms, uncorrectable electrolyte abnormalities, or concomitant drugs that prolong the QT interval: not recommended. Monitor electrolytes before therapy and after dose adjustments. Monitor ECG at Day 15 of treatment, monthly during the 1^st 3 months, then every 3 months thereafter, or more as needed. If QTc >500ms, interrupt therapy, correct electrolytes, and control cardiac risk factors. Severe hepatic or renal impairment. Monitor liver enzymes, bilirubin before therapy and monthly, or as needed. Monitor for ophthalmologic reactions routinely. Avoid sun exposure. Pregnancy (Cat. D); avoid. Use adequate contraception during therapy and for at least 2 months after. Nursing mothers: not recommended.

Interaction(s):

Concomitant CYP3A4, CYP1A2 or CYP2D6 substrates with narrow therapeutic indices: not recommended; if CYP1A2 or CYP2D6 substrates unavoidable, consider dose reduction of substrates. Caution with concomitant strong CYP3A4 inhibitors (eg, azole antifungals, clarith­romycin) or inducers (eg, phenytoin, rifampin). May potentiate warfarin; monitor INR.

Adverse Reaction(s):

Arthralgia, rash, alopecia, fatigue, photosensitivity, nausea, pruritus, skin papilloma; cuSCC, severe hypersensitivity or dermatologic reactions (discontinue if occurs), prolonged QTc, uveitis.

How Supplied:

Tabs—120

Last Updated:

11/11/2011

FDA批准Zelboraf (vemurafenib)用于晚期皮肤癌治疗及其伴随诊断测试
FDA approves Zelboraf and companion diagnostic test for late-stage skin cancer
FDA批准Zelboraf联合诊断试验用于晚期皮肤癌。
Second melanoma drug approved this year that improves overall survival
今年批准了第二种黑色素瘤治疗药物，提高了整体生存率
The U.S. Food and Drug Administration today approved Zelboraf (vemurafenib), a drug to treat patients with late-stage (metastatic) or unresectable (cannot be removed by surgery) melanoma, the most dangerous type of skin cancer.
USFDA今天批准Zelboraf (vemurafenib)，一种用于治疗晚期（转移性）或者不能切除（不能手术切除）的黑色素瘤，是一种一种最危险的皮肤癌。
Zelboraf is specifically indicated for the treatment of patients with melanoma whose tumors express a gene mutation called BRAF V600E. The drug has not been studied in patients whose melanoma tests negative for that mutation by an FDA approved diagnostic.
Zelboraf特别用于治疗这些患有黑色素瘤的患者，有着称作为BRAF V600E的肿瘤基因表达。该药尚未在黑色素瘤FDA诊断为突变阴性的患者中进行研究。
Zelboraf is being approved with a first-of-a-kind test called the cobas 4800 BRAF V600 Mutation Test, a companion diagnostic that will help determine if a patient’s melanoma cells have the BRAF V600E mutation.
Zelboraf正在批准一个第一类试验，名为cobas 4800 BRAF V600 突变试验，联合诊断用于测定患者突变细胞发生BRAF V600E突变。
The BRAF protein is normally involved in regulating cell growth, but is mutated in about half of the patients with late-stage melanomas. Zelboraf is a BRAF inhibitor that is able to block the function of the V600E-mutated BRAF protein.
BRAF蛋白通常是参与调节细胞生长，但在晚期黑色素瘤患者中，约半数出现突变。Zelboraf是一种BRAF抑制剂，能阻断V600E-突变的BRAF蛋白的功能。
“This has been an important year for patients with late-stage melanoma. Zelboraf is the second new cancer drug approved that demonstrates an improvement in overall survival,” said Richard Pazdur, M.D., director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research. “In March, we approved , another new treatment for late-stage melanoma that also showed patients live longer after receiving the drug.”
“这对晚期黑色素瘤患者来说是Zelboraf是第二个新型的获得批准的癌症药物，可提高整体生存率，”FDA的CDER抗肿瘤药物办公室负责人Richard Pazdur, M.D.如是说。“3月份，我们批准了Yervoy (ipilimumab)，另一个新型治疗晚期黑色素瘤药物，可延长服药患者的生存时间。”
Zelboraf was reviewed under the FDA’s priority review program that provides for an expedited six-month review of drugs that may offer major advances in treatment or that provide a treatment when no adequate therapy exists. Zelboraf and the companion BRAF V600E test are being approved ahead of the drug’s Oct. 28, 2011 goal date and the companion diagnostics’ Nov. 12, 2011 goal date.
Zelboraf进入FDA的优先审查程序，进行了加速6个月的药物审批，可以提高治疗进展或者在没有缺少治疗的情况下，提供治疗。
Zelboraf’s safety and effectiveness were established in a single international trial of 675 patients with late-stage melanoma with the BRAF V600E mutation who had not received prior therapy. Patients were assigned to receive either Zelboraf or dacarbazine, another anti-cancer therapy. The trial was designed to measure overall survival (the length of time between start of treatment and death of a patient).
Zelboraf的安全性和有效性已被公开，在一项单独的国际试验中，有675例晚期黑色素瘤患者参与，这些患者因BRAF V600E突变而不能接受优先治疗。患者被安排服用Zelboraf或达卡巴嗪，另一种抗癌治疗。该试验设计目的是测定总体生存期（从治疗开始到患者死亡的时长）。
The median survival (the length of time a patient lives after treatment) of patients receiving Zelboraf has not been reached (77 percent still living) while the median survival for those who received dacarbazine was 8 months (64 percent still living).
服用Zelboraf的患者平均生存期（治疗后患者时长）（77%存活）没有达到服用达卡巴嗪患者8个月的平均生存期（64%存活）。
“Today’s approval of Zelboraf and the cobas test is a great example of how companion diagnostics can be developed and used to ensure patients are exposed to highly effective, more personalized therapies in a safe manner,” said Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostic Device Evaluation and Safety in the FDA’s Center for Devices and Radiological Health.
“今日批准的Zelboraf和cobas试验，可以作为一个很好的实例，在安全的方式下，开发和使用联合诊断，以确保患者高效、更个性化的治疗，”FDA的器械和放射学健康中心的体外诊断器械评价办公室负责人Alberto Gutierrez, Ph.D.如是说。
The FDA’s approval of the cobas 4800 BRAF V600 Mutation Test was based on data from the clinical study that also evaluated the safety and effectiveness of Zelboraf. Samples of a patient’s melanoma tissue were collected to test for the mutation.
FDA批准的cobas 4800 BRAF V600突变实验是建立在Zelboraf的临床试验评价的安全性和有效性的数据基础上的。收集黑色素瘤患者的组织进行突变试验。
The most common side effects reported in patients receiving Zelboraf included joint pain, rash, hair loss, fatigue, nausea, and skin sensitivity when exposed to the sun. About 26 percent of patients developed a skin-related cancer called cutaneous squamous cell carcinoma, which was managed with surgery. Patients treated with Zelboraf should avoid sun exposure.
服用Zelboraf治疗患者的最常见的不良反应有疼痛、皮疹、脱发、疲劳、恶心和皮肤日光过敏。约有26%的患者出现皮肤相关性癌症，称作皮肤鳞状细胞癌，可经手术治疗。患者在服用Zelboraf时应避免接触日光。
Zelboraf is being approved with a Medication Guide to inform health care professionals and patients of Zelboraf’s potential risks.
Zelboraf批准时，用药指南中告知医疗专业人员和患者Zelboraf的潜在风险。
In July 2011, the FDA issued a new draft guidance to facilitate the development and review of companion diagnostics. The guidance, currently available for public comment, is intended to provide companies with guidance on the agency’s policy for reviewing a companion diagnostic and the corresponding drug therapy.
2011年7月，FDA发布一项指导原则草案，促进联合诊断的开发和审评。指导原则，目前征求意见中，目的是为企业和监管部门审评联合诊断和药物相关性治疗的指导原则。
Melanoma is the leading cause of death from skin disease. The National Cancer Institute estimated that 68,130 new cases of melanoma were diagnosed in the United States during 2010; about 8,700 people died from the disease.
黑色素瘤是一种可导致死亡的皮肤病。国立癌症研究所评价，2010年US有68 130新增病例被诊断为黑色素瘤；约8 700例死于此病。