CHICAGO (EGMN) – Vandetanib, a multitargeted experimental agent, significantly delayed progression of locally advanced or metastatic medullary thyroid cancer in a randomized, placebo-controlled, phase III trial.

At a median of 2 years’ follow-up, median progression-free survival had not been reached in 231 patients who were treated with vandetanib, but was 19.3 months in 100 patients on placebo. Only 32% of the vandetanib arm had disease progression vs. 51% of the control group (hazard ratio, 0.46; P less than .0001).

“Vandetanib demonstrated efficacy in this study of patients with advanced metastatic medullary thyroid cancer, a stage of disease for which there is currently no effective therapy,” said principal investigator Dr. Samuel A. Wells, who presented the data at the annual meeting of the American Society of Clinical Oncology.

Vandetanib targets the VEGF (vascular endothelial growth factor), EGFR (epidermal growth factor receptor) and RET (rearranged during transfection) pathways. In a previous phase II study, the drug demonstrated antitumor activity in patients with advanced hereditary medullary thyroid cancer, a rare disease (Cancer Res. 2002;62:4645-55; Cancer Res. 2002;62:7284-90; J. Clin. Oncol. 2010;28:767-72).

Dr. Wells, head of the thyroid clinical research program at the U.S. National Cancer Institute, reported that the ZETA (Zactima [vandetanib’s U.S. brand name] Efficacy in Thyroid Cancer Assessment) trial randomized 331 patients in a 2:1 ratio to vandetanib 300 mg per day or to placebo from December 2006 through November 2007. At the time of the data cutoff on July 31, 2009, 124 (37%) patients had progressed, 48 (15%) were deceased, and 102 (31%) had received open-label vandetanib after progression. The last group included 52 patients from the placebo arm, who crossed over to the active compound in an optional open-label phase of the study.

Men accounted for slightly more than half of both arms of the trial. The mean age in the treatment arm was 50.7 years vs. 53.4 years in the placebo arm. More than 90% of both arms had metastatic disease.

In an intent-to-treat analysis, vandetanib produced an objective response rate of 45% vs. 13% with placebo (odds ratio, 5.48; P less than .0001). Dr. Wells noted that 12 of 13 responses in the placebo arm were achieved after patients crossed over to vandetanib. He also reported that when open-label patients were excluded, vandetanib’s advantage in progression-free survival increased to a hazard ratio of 0.27 (P less than .0001).

Time to worsening of pain was significantly longer in the treatment arm: a median of 7.85 months vs. 3.25 months in the placebo arm (HR, 0.61; P = 0.006).

Diarrhea (56%), rash (45%), nausea (33%), and hypertension (32%) of any grade were more frequent with vandetanib. About 35% of patients on the active drug required dose reductions, and 28 patients (12%) discontinued treatment due to adverse events. The most common grade 3 and higher adverse events were diarrhea in 25 patients (11%), hypertension in 20 (9%), ECG QT prolongation in 18 (8%) and fatigue in 13 (6%) patients treated with the investigational drug.

Toxicity was generally manageable, Dr. Wells said, permitting treatment with vandetanib for long periods of time.

Vandetanib 300 mg has orphan drug designation in the United States and Europe for the treatment of patients with advanced medullary thyroid cancer. AstraZeneca plans regulatory submissions in 2010, according to a company spokesperson.

“This trial completely blew me away,” said invited discussant Dr. A. Dimitrios Colevas of the cancer center at Stanford (California) University, who commented on accrual in the 331-patient trial. “The fact that they put together an effort like that is in itself worth an amazing amount of praise.”

Dr. Colevas noted the rarity of this disease: “The first question is, How many of us treat medullary thyroid cancer at all? It’s an extremely rare disease.”

He also expressed some concern about toxicity in a trial that focused on progression-free survival and not overall survival.

“Do we really need to treat these people the whole time, or is there benefit from short term of treatment, or is there going to be some kind of rebound/relapse/explosion of disease? “ he asked. “That question is still on the table but will be impossible to answer in this rare disease.”

AstraZeneca, maker of vandetanib, sponsored the trial. Dr. Wells disclosed being scientific advisor to AstraZeneca. Dr. Colevas disclosed no relevant financial relationships.

Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

芝加哥(EGMN)——一项随机、安慰剂对照的III期临床试验结果显示，凡德他尼(一种针对多个靶点的试验药)可显著延缓局部晚期或转移性甲状腺髓样癌发生进展的时间。

 

在中位随访2年时，接受凡德他尼治疗的患者中共有231例未能达到中位无进展生存期，但在100例安慰剂组患者中该数值为19.3个月。凡德他尼组患者出现疾病进展的几率仅为32%，而对照组患者的这一数值为51%(危险比为0.46；P<0.0001)。

 

该研究的主要作者Samuel A. Wells 博士在美国临床肿瘤学会年会上提交这一数据时发言说：“在该研究中，研究者证实了凡德他尼对晚期转移性甲状腺髓样癌患者有效，目前还没有针对这一阶段疾病的有效治疗方案。”

 

凡德他尼的作用靶点是VEGF (血管内皮生长因子)、EGFR (表皮生长因子受体)和RET(基因转染过程中可以重排的基因)通路。在之前进行的一项II期研究中，研究者业已证实，在晚期遗传性甲状腺髓样癌(这种疾病极为罕见)患者中应用该药可以产生抗肿瘤活性(Cancer Res. 2002;62:4645-55; Cancer Res. 2002;62:7284-90; J. Clin. Oncol. 2010;28:767-72)。

 

美国国家癌症研究所甲状腺临床研究项目的负责人Wells博士报告说ZETA[Zactima(凡德他尼在美国的商品名)对甲状腺癌的疗效评估]试验将331例患者按2∶1的比例随机分配至服用300 mg/天凡德他尼组或安慰剂组，试验时间为2006年12月至2007年11月。到2009年7月31日数据截止时为止，共有124例37%)患者出现疾病进展，48例(15%)患者死亡，还有102例患者在疾病进展后开始接受开放性凡德他尼治疗。最后一组包括53例来自安慰剂组的患者，他们在该研究的自主开放阶段转为接受这种活性化合物治疗。

 

在该试验的两组患者中男性所占比例均略过半。治疗组患者的平均年龄为50.7岁，而安慰剂组患者为53.4岁。两组患者中存在疾病转移的比例均超过90%。

 

对意向性治疗所进行的分析表明，凡德他尼的客观有效率为45%，而安慰剂组为13%(比值比为5.48；P<0.0001)。Wells博士指出，在患者转为接受凡德他尼治疗后，该药对安慰剂组13例患者中的12例有效。他还报告说当研究者将开标性的患者排除在外后，凡德他尼在患者无进展生存期这一指标上存在的优势增加了，其危险比(HR)为0.27(P<0.0001)。

 

治疗组患者出现疼痛加剧的时间显著更长：其中位时间为7.85个月，而安慰剂组为3.25个月(HR=0.61；P=0.006)。

 

使用凡德他尼的患者出现腹泻(56%)、皮疹(45%)、恶心(33%)和任一级别高血压(32%)的几率都更高。在使用这一活性药物的患者中大约有35%需要减量，还有28例患者因不良事件而停止治疗。在接受这种试验药物治疗的患者中，最常见的3级及3级以上不良事件为腹泻(25例，11%)、高血压(20例，9%)、心电图(ECG)QT间期延长(18例，8%)以及乏力(13例，6%)。

 

Wells博士说，该药物的毒性作用通常是可治疗的，这就使得凡德他尼长期治疗成为可能。

 

凡德他尼已获得美国和欧洲晚期甲状腺髓样癌治疗的孤儿药物资格。据阿斯利康公司的某位发言人称，该公司计划于2010年向管理机构进行申报。

 

加利福尼亚州斯坦福大学癌症中心的特邀评论员A. Dimitrios Colevas博士就这项纳入331例患者的临床试验的患者招募工作发表评论时说：“该试验令我感到震惊，该试验的研究人员如此的齐心协力，这本身就是一个值得赞美的惊人数量。”

 

Colevas博士指出该疾病极为罕见：“首要问题是，我们总共能治疗多少甲状腺髓样癌患者呢？它是一种极其罕见的疾病。”

 

他同时表示，对于这样一项关注无进展生存期而不是总体生存期的试验，该药物的毒性令人担忧。

 

他质疑说：“我们真的需要对这些患者进行全程治疗吗？还是短期治疗也可以使患者获益呢？此外，该疾病是否会出现某种反弹/复发/剧烈发作呢？这一问题尚处于讨论中，但就这一罕见疾病而言，我们将可能无法作出回答。”

 

凡德他尼的制造商阿斯利康公司是该试验的赞助方。Wells博士披露说其目前担任阿斯利康公司的科学顾问。Colevas博士披露说无相关经济关系。

 

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