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英文药名：ZELBORAF（vemurafenib tablet）
中文药名：威罗菲尼片
生产厂家：罗氏制药
药品介绍
美国食品药品监督管理局（FDA）于2011年8月17日批准瑞士罗氏制药公司产品Vemurafenib（商品名：ZELBORAF）用于治疗BRAFV600E基因突变型（用FDA批准的方法检测）不可切除或转移性黑色素瘤。需要注意的是，不建议将该药用于野生型BRAF黑色素瘤患者。
FDA的药物评价和研究中心肿瘤药品办公室主任Richard Pazdur, M.D.说“"对有后期黑色素瘤患者今年是重要一年。Zelboraf是证实改善总生存的第二个被批准新抗癌药物” “3月我们批准了Yervoy(ipilimumab)，为后期黑色素瘤另一个新治疗，接受药物后也显示延长患者生存。”
FDA的设备和放射健康部中的在体外诊断设备评价和安全性办公室主任Alberto Gutierrez, Ph.D说：“今天批准的Zelboraf和cobas检验是发展伴随诊断和使用以保证患者以安全方式被暴露至高度有效，更个体化治疗一个大实例。”
Manufacturer:
Genentech, Inc.
Pharmacological Class:
Kinase inhibitor.
Active Ingredient(s):
Vemurafenib 240mg; tabs.
Indication(s):
Treatment of unresectable or metastatic melanoma with BRAFV600E 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 BRAFV600E. 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 BRAFV600E.
Clinical Trials:
The efficacy and safety of vemurafenib in patients with treatment naive, BRAFV600E 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 BRAFV600E 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 1st 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
Related Disease:
Melanoma
包装规格：
美国
240mg*120片/瓶
德国、英国
240mg*56片/盒
罗氏组合疗法Cotellic/Zelboraf大幅改善BRAF突变阳性晚期黑色素瘤总生存期
2015年11月24日，瑞士制药巨头罗氏（Roche）研发的一款口服靶向抗癌新药Cotellic（cobimetinib）获美国FDA批准，联合罗氏自身已上市抗癌药Zelboraf（vemurafenib，威罗菲尼），用于BRAF V600E或V600K突变阳性不可切除性或转移性黑色素瘤患者的治疗。该药也标志着罗氏在过去5年中获得FDA批准的第7个新药。在欧盟方面，Cotellic预计将在2015年底拿到上市批文。
近日，罗氏在2015年黑色素瘤研究学会（SMR）国际会议上公布了有关Cotellic的一项关键III期coBRIM研究的新数据，这些数据进一步加强了Cotellic+Zelboraf组合疗法针对BRAF V600突变阳性晚期黑色素瘤的临床疗效，尤其是患者总生存方面。
该研究是一项国际、随机、双盲、安慰剂对照III期研究，在495例先前未经治疗的、携带BRAF V600突变的不可切除性局部晚期或转移性黑色素瘤患者中开展，调查了Cotellic（60mg剂量，每天一次）联合Zelboraf（960mg剂量，每天2次）的疗效和安全性。数据显示，与Zelboraf+安慰剂治疗组相比，Cotellic+Zelboraf联合治疗组死亡风险显著降低30%（中位总生存期OS：22.3个月 vs 17.4个月，p=0.005）。而此前公布的数据显示，与Zelboraf+安慰剂治疗组相比，Cotellic+Zelboraf联合治疗组疾病恶化风险显著降低，无进展生存期（中位PFS：12.3个月 vs 7.2 个月，p＜0.001）显著延长。
5年前，BRAF突变阳性晚期黑色素瘤患者的总生存期不过数月而已；而该项研究中，Cotellic+Zelboraf联合治疗组一年存活率高达74.5%，二年存活率高达48.3%。罗氏表示，将把coBRIM研究的最终OS数据提交至美国及欧盟药品监管部门。
关于Cotellic（cobimetinib）：
cobimetinib是一种口服小分子MEK抑制剂，MEK是一种蛋白激酶，是RAS-RAF-MEK-ERK信号通路的一部分，该通路可促进细胞的分裂和存活，在人类癌症（包括黑色素瘤）中往往处于激活状态。cobimetinib旨在选择性阻断MEK蛋白的活性，从而阻断其下游的信号通路传导。
目前，罗氏也正在调查cobimetinib联合其他药物（包括免疫疗法）用于多种类型肿瘤的治疗潜力，包括非小细胞肺癌（NSCLC）、结肠癌、三阴乳腺癌和黑色素瘤。 | 
