欧盟委员会已批准诺华生产的Afinitor（依维莫司）片剂用于晚期肾细胞癌（RCC）患者的治疗，欧洲医学肿瘤学会等欧洲几项权威治疗指南进行更新，推荐该药物作为晚期肾癌患者的二线治疗药。

据诺华肿瘤事业部总裁兼首席执行官David Epstein介绍，目前全球所有肾细胞癌患者中，将近40%的患者在确诊时就已处于癌症晚期，意味着肿瘤已扩散到肾脏以外。根据标准治疗方案，这些患者的初始治疗可能包括VEGF－靶向治疗。在依维莫司批准上市之前，对采用靶向治疗或治疗后出现癌症进展的晚期肾细胞癌患者来说，没有其他的治疗选择。

“这项欧盟决议将适用于所有27个欧盟成员国。”David Epstein称，Afinitor（依维莫司）片剂获得欧盟批准上市，是以一项关键性的III期试验为依据的，该试验显示在采用VEGF靶向治疗后疾病出现进展的晚期肾癌患者中，Afinitor治疗组的无肿瘤生长或死亡的中位时间比安慰剂组延长一倍以上（4.9个月：1.9个月），使疾病进展或死亡风险降低67%。据了解，共有416名晚期RCC患者参加了这项跨国、多中心、随机、双盲临床试验。

此外，包括来自欧洲泌尿学会（EAU）、西班牙肿瘤泌尿生殖小组（SOGUG）、欧洲癌症研究和治疗组织（EORTC）、欧洲医学肿瘤学会（ESMO）的治疗指南以及英国共识性指南在内的几项欧洲治疗指南已进行更新，推荐将Afinitor作为靶向治疗后病情进展的晚期肾癌患者的二线治疗药物。

AFINITOR

Indication(s):

Advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib.

Pharmacology:

The mammalian target of rapamycin, mTOR, is a serine-threonine kinase involved in a cellular process that has been shown to be deregulated in several human cancers. Everolimus is a rapamycin derivative that binds to an intracellular protein, forming a complex that inhibits mTOR kinase activity. It also reduces the activity of S6 ribosomal protein kinase and eukaryotic elongation factor 4E-binding protein, which are two other factors involved in protein synthesis in the mTOR pathway. In addition, it reduces the expression of both vascular endothelial growth factor and hypoxia-inducible factor. The inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake.

Clinical Trials:

A study that compared everolimus to placebo, in conjunction with best supportive care, was undertaken in patients with metastatic renal cell carcinoma whose disease had progressed despite prior treatment with sunitinib, sorafenib, or both sequentially. The use of everolimus was shown to be superior to placebo for progression-free survival, which was assessed via a blinded, independent, central radiologic review. The median duration of progression-free survival for 277 patients taking everolimus was 4.9 months, versus 1.9 months for 139 patients given placebo. The treatment effect was similar across prognostic scores and prior treatment with sunitinib and/or sorafenib.

Legal Classification:

Rx

Adults:

Swallow whole with water. 10mg once daily. Moderate hepatic dysfunction (Child-Pugh class B), or adverse reactions: reduce to 5mg once daily. Concomitant strong CYP3A4 inducers: may increase to 15–20mg once daily. Continue as long as benefit observed or until unacceptable toxicity occurs.

Children:

Not recommended.

Contraindication(s):

Sirolimus, temsirolimus, rapamycin allergy.

Precaution(s):

Severe hepatic impairment (Child-Pugh class C): not recommended. Moderate hepatic impairment: reduce dose. Pre-existing invasive fungal infections: treat before starting. Monitor CBCs, renal function, lipids, blood glucose, and for pneumonitis and infections. Pregnancy (Cat.D), nursing mothers: not recommended.

Interaction(s):

Avoid live vaccines. Potentiated by moderate to strong CYP3A4 inhibitors, P-glycoprotein inhibitors; avoid (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, fosamprenavir, voriconazole, aprepitant, erythromycin, fluconazole, grapefruit juice, verapamil, diltiazem). Antagonized by strong CYP3A4 inducers; avoid (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital); increase everolimus dose if used.

Adverse Reaction(s):

Pneumonitis (reduce dose and/or manage with corticosteroids), infections (discontinue if invasive systemic fungal infection develops), stomatitis (treat with non-alcoholic, non-peroxide mouthwash), asthenia, fatigue, cough; increased serum creatinine, blood glucose, lipids; decreased hemoglobin, platelets, neutrophils, serum phosphate; others (see literature).

How Supplied:

Tabs—28

Last Updated:

4/17/2009