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Information on Vandetanib Vandetanib (rINN, proposed trade name Zactima), also known as ZD6474, is an antagonist of the vascular endothelial growth factor receptor (VEGFR) and the epidermal growth factor receptor (EGFR). It is a tyrosine kinase inhibitor. Current status 1. 治疗晚期NSCLC（非小细胞肺癌）003号研究比较了凡德他尼 300 mg/d和吉非替尼250 mg/d对一线或二线化疗失败的168例晚期NSCLC病人的疗效，与吉非替尼相比，凡德他尼明显地增加了有效率和延长了疾病无进展生存时间，分别为8%和1%，11.9周和8.1周，(P=0.011)。在临床试验中如果病人病情进展或不能耐受毒性，允许其改变治疗方案。试验结果表明，用吉非替尼代替凡德他尼的病人疾病控制率为14%，而用凡德他尼代替吉非替尼的病人疾病控制率达到32%，预计中位总生存期由凡德他尼→吉非替尼为6.1个月，而由吉非替尼→凡德他尼为7.4个月。0007号研究正在进行中，目的是评价凡德他尼联合紫杉醇(200 mg/m2)+卡铂(AUC=6)一线治疗ⅢB-IV期NSCLC的疗效。初步试验结果显示，凡德他尼可同时联合传统的化疗药物治疗NSCLC，没有明显增加3~4度的不良反应。 2. 治疗晚期乳腺癌46例，既往接受紫杉醇+蒽环类化疗失败的转移性乳癌患者，接受凡德他尼(100 mg或300 mg)，44例可评价的患者中未见客观疗效，2组病人各有1例病情稳定(SD)≥24周，作者认为单药凡德他尼治疗复发耐药的乳腺癌疗效有限，但耐受性良好。 3. 治疗晚期多发性骨髓瘤，18例化疗或造血干细胞移植治疗失败的多发性骨髓瘤患者，口服凡德他尼(100 mg)3~29.4周，球蛋白或尿M蛋白未见改善，毒副作用可耐受，常见的毒副作用包括恶心、呕吐、腹泻、皮疹、皮肤瘙痒、感觉障碍等，但未见明确的QT间期改变。 4. 治疗甲状腺癌甲状腺髓样癌发病率低，具有遗传性，无论放射治疗、联合化疗抑或内分泌治疗效果不佳，预后差。0008号研究是一项进行中的、开放的Ⅱ期研究，评估凡德他尼治疗进展期遗传性甲状腺髓样癌的疗效和毒副作用。11例可评价的病人中(接受凡德他尼 300 mg/d，至少3个月)，2例患者获得PR，9例患者获SD。另外，病人血浆肿瘤标志物降钙素和癌胚抗原分别较基线值下降了72%和25%。目前人们认为，凡德他尼治疗甲状腺髓样癌主要作用于肿瘤细胞靶点RET酪氨酸激酶，RET可促进肿瘤细胞生长和存活，40%的散发性和100%遗传性甲状腺髓样癌有RET基因的过表达。 适应证和用途 因为vandetanib治疗相关风险，在惰性，无症状或缓慢进展疾病患者中使用vandetanib应谨慎小心考虑。 剂量和给药方法 剂型和规格 禁忌证 警告和注意事项 不良事件 药物相互作用 On April 6, 2011, the U. S. Food and Drug Administration approved vandetanib tablets (Vandetanib Tablets, AstraZeneca Pharmaceuticals LP), a kinase inhibitor, for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable, locally advanced, or metastatic disease. The use of vandetanib in patients with indolent, asymptomatic or slowly progressing disease should be carefully considered because of the treatment-related risks of vandetanib. The approval was based on an international, multicenter, randomized, double-blind trial conducted in patients with unresectable locally advanced or metastatic medullary thyroid carcinoma. Patients were randomized (2:1) to receive either vandetanib, 300 mg/day orally, (n=231) or placebo (n=100). The primary objective was demonstration of improvement in progression-free survival (PFS) with vandetanib compared to placebo. Other endpoints included evaluation of overall survival (OS) and objective response rate (ORR). A central, independent blinded review of the imaging data was used in the assessment of PFS and ORR. Upon objective disease progression by the investigator, patients were given the option of receiving open-label vandetanib. An improvement in PFS was observed for patients randomized to receive vandetanib (HR=0.35; 95% CI: 0.24, 0.53; p<0.0001). Analyses in the subgroups who were either symptomatic or who had disease progression within 6 months prior to enrollment showed similar PFS results: hazard ratios of 0.31 (95% CI: 0.19, 0.53) and 0.41 (95% CI: 0.25, 0.66), respectively. At the primary PFS analysis, 15% of the patients had died; no significant OS difference was noted. The ORR was 44% versus 1% for patients randomized to receive vandetanib or placebo, respectively. All objective responses were partial responses. QT prolongation, torsades de pointes, and sudden death are included in a boxed warning. Because of vandetanib’s prolonged half-life of 19 days, ECGs and levels of serum potassium, calcium, magnesium and TSH should be obtained at baseline, at 2-4 weeks and 8-12 weeks after starting treatment and subsequently every 3 months. Electrolytes and ECGs may require more frequent monitoring in patients experiencing diarrhea. Only prescribers and pharmacies certified through the Vandetanib Risk Evaluation Mitigation Strategy Program, a restricted distribution program, are able to prescribe and dispense vandetanib. The most common (≥ 20%) grade 1-4 adverse reactions included diarrhea/colitis, rash, dermatitis acneiform, nausea, hypertension, headache, fatigue, decreased appetite, and abdominal pain. Laboratory abnormalities in > 20% of patients included decreased calcium, increased ALT, and decreased glucose. The most common (≥ 5%) grade 3-4 adverse reactions were diarrhea/colitis, hypertension and hypertensive crisis, QT prolongation, fatigue, and rash. Adverse reactions resulting in death in patients receiving vandetanib (n=5) were respiratory failure, respiratory arrest, aspiration pneumonia, cardiac failure with arrhythmia, and sepsis. In addition, two deaths in patients receiving vandetanib (one sudden death and one death from cardiopulmonary arrest) were noted after data cut-off. The recommended daily dose of vandetanib is 300 mg orally. The starting dose should be reduced to 200 mg in patients with moderate (creatinine clearance ≥30 to <50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment. -------------------------------------------------------------------
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