ORLANDO (EGMN) – Adding vandetanib, a novel once-daily oral agent, to docetaxel in the second-line treatment of advanced non–small cell lung cancer resulted in a small but statistically significant improvement in progression-free survival in the phase III ZODIAC trial in 1,391 patients.
The regimen was associated with a median progression-free survival of 4.0 months vs. 3.2 months with docetaxel (Taxotere) and placebo (hazard ratio, 0.79; P less than .001) at a median follow-up of 12.8 months.
“Vandetanib is the first oral targeted therapy, or perhaps the first therapy at all, in phase III to show significant evidence of clinical benefit when added to standard chemotherapy in patients with previously treated non–small cell lung cancer [NSCLC],” principal investigator Dr. Roy S. Herbst said at the annual meeting of the American Society of Clinical Oncology.
When asked at a press briefing about the clinical significance of this slight prolongation, Dr. Herbst said that one of the keys to the ZODIAC (Zactima in Combination with Docetaxel in Non–Small Cell Lung Cancer) trial is a significant delay in patient-reported, disease-related symptoms such as cough, shortness of breath, and pain (HR, 0.77; P less than .001).
“We were able to show that with this increase in time for a patient’s tumor to grow, they’re also reporting they’re feeling better,” said Dr. Herbst, professor and chief of thoracic/head and neck medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston. “That’s a small step. Do we want more? Absolutely.”
Dr. Martin J. Edelman, who was invited to discuss the study, noted that benefits were seen across most subgroups. Nonsmokers made up only 25% of the population because of heavy Asian accrual; however, nonsmokers typically account for even fewer (10%-15%) of NCSLC patients in the United States.
Only 3% of patients received first-line bevacizumab, he continued, so its influence on the utility of vandetanib in second-line therapy is unclear. Finally, no data were provided on subsequent therapy, and additional therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors could substantially alter the outcome, said Dr. Edelman of the University of Maryland Medical Center in Baltimore.
Study sponsor AstraZeneca Pharmaceuticals has announced that it plans to file a regulatory submission for vandetanib (Zactima) in the first half of 2009.
ZODIAC investigators randomized patients at 250 centers throughout Europe, the Americas, and Asia Pacific (694 patients to 100 mg of vandetanib daily plus 75 mg/m2 of docetaxel for a maximum of six 21-day cycles, and 697 to docetaxel alone). Their median age was 59 years, 59% were Caucasian, 37% were East Asian, and 64% had a World Health Organization performance status of 1.
The adverse event profile in ZODIAC was consistent with that observed in other vandetanib studies in NSCLC. There was no increase in hemoptysis or CNS bleeds in the vandetanib arm. The incidence of QTc prolongation was less than 2% in patients receiving vandetanib.
Data from ZEAL, a smaller phase III study sponsored by AstraZeneca, was also presented at the meeting. It showed that the addition of vandetanib to pemetrexed (Alimta) did not significantly improve the primary end point of progression-free survival in 534 patients with previously treated advanced NSCLC. Median progression-free survival reached 17.6 weeks with vandetanib and pemetrexed vs. 11.9 weeks for pemetrexed alone (HR, 0.86; P = .108).
Dr. Edelman speculated that there may be a biological rationale for why antiangiogenic therapy may work better with a taxane-based therapy (such as docetaxel) than with other therapies. In the preclinical setting, data suggest that taxane therapy can induce circulating endothelial progenitor cells, which selectively migrate to tumors and repopulate the population, resulting in accelerated tumor growth (Cancer Cell. 2008;14:263-73).
“They have evidence for this with gemcitabine; they have not done any work with pemetrexed,” said Dr. Edelman. “So this is very speculative in this particular situation.”
Overall survival showed a positive trend favoring vandetanib in both studies, but did not reach statistical significance in either ZODIAC (HR, 0.91; P = .196) or ZEAL (HR, 0.86; P = .219).
In both trials, the addition of vandetanib 100 mg once daily significantly improved objective response rate (in ZODIAC, 17% vs. 10%; P less than .001; in ZEAL, 19% vs. 8%; P less than .001). Patients in ZEAL also reported a longer time to deterioration of disease-related symptoms (HR, 0.71; P = .005).
Data from ZEST, another phase III AstraZeneca trial presented at the meeting, showed that vandetanib failed to significantly prolong progression-free survival, compared with erlotinib in 1,240 patients with previously treated advanced NSCLC (11.3 weeks vs. 8.9 weeks; HR, 0.98; P = .721). However, vandetanib given at 300 mg/day and erlotinib at 150 mg/day showed similar efficacy for progression-free and overall survival in a preplanned noninferiority analysis.
There was no difference in the secondary end points of overall survival, overall response rate, or time to deterioration of symptoms for patients who were treated with vandetanib vs. erlotinib. The incidence of adverse events leading to death was higher with vandetanib (5.6% vs. 2.9%).
Results are expected in the second half of 2009 from the phase III ZEPHYR trial of 300 mg/day vandetanib monotherapy plus best supportive care vs. best supportive care in patients with locally advanced or metastatic NSCLC that has not responded to anti-EGFR therapy.
The ZODIAC investigators disclosed receiving research funding and honoraria and working as employees or consultants for AstraZeneca Oncology. They also have worked as consultants for Genzyme Corp., own stock in Takeda Pharmaceutical Co., and have received research funding from Chugai Taiho, Takeda, and Wyeth.
The ZEAL investigators disclosed employment, advisory roles, stock ownership, honoraria, and research funding ties with AstraZeneca.
The ZEST investigators disclosed employment, advisory roles, honoraria, and research funding ties with AstraZeneca. They also have received honoraria from Eli Lilly and Co., Pfizer Oncology, and Roche, and research funding from Bayer.
Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
奥兰多(EGMN)——ZODIAC Ⅲ期临床试验发现，对晚期非小细胞肺癌(NSCLC)患者，在应用多西紫杉醇的二线治疗中加用vandetanib(一种新型的每日1次口服制剂)，可使患者疾病无进展生存有轻微但具统计学意义的改善，此项研究包括1,391例患者。
所有患者的中位随访期为12.8个月，接受此治疗方案的患者的中位疾病无进展生存期为4.0个月，而接受多西紫杉醇+安慰剂方案者为3.2个月(风险比HR=0.79，P<0.001)。
主要研究者Roy S. Herbst在美国临床肿瘤学会的年会上表示：“在此项Ⅲ期研究中，对之前接受过治疗的NSCLC患者进行的规范化疗加用的药物中，vandetanib是第一种口服靶向药物，或许直接可以说是第一种真正表现出显著临床获益的药物。”
在新闻发布上，当被问及这一生存期的轻微延长的临床意义时，Herbst博士说，ZODIAC(Zactima 联合多西紫杉醇治疗NSCLC)研究的一个关键是，患者报告与疾病相关的症状的发生时间明显延后，如咳嗽、气短和疼痛(HR=0.77，P<0.001)。
Herbst博士说：“我们发现，肿瘤生长延缓的同时，患者自身感觉也更好。这只是一小步，我们当然需要更进一步。”Herbst博士是得克萨斯大学位于休斯敦的MD Anderson肿瘤中心胸部/头颈肿瘤科主任和教授。
受邀参加讨论此项研究的Martin J. Edelman博士指出，这一获益在每个亚组均有显现。因为入选的亚洲人吸烟人数多，本研究中不吸烟者仅占25%，而在美国NSCLC患者中不吸烟者所占比例更低，仅10%~15%。
来自位于巴尔的摩的马里兰大学医学中心Edelman博士还指出，仅3%的患者接受贝伐单抗的一线治疗，所以它对二线治疗中应用vandetanib的影响尚不清楚。而对于应用表皮生长因子受体(EGFR)酪氨酸激酶抑制剂的后续(附加)治疗可显著改变预后的资料更是无从获得。。
此项研究的资助者是阿斯利康制药公司，该公司已宣布计划于2009年上半年提交vandetanib (Zactima)新药注册申请。
ZODIAC研究者们将来自欧洲、美洲和亚太地区的患者随机分成两组：一组694例，接受每日100 mg vandetanib外加75 mg/m2的多西紫杉醇治疗；另一组697例，仅应用多西紫杉醇治疗；每组至少治疗6个疗程，每个疗程21天。患者中位年龄59岁，59%为白人，37%为东亚人。64%的患者为世界卫生组织1级临床表现。
ZODIAC研究中发现的药物不良反应与其他在NSCLC中进行的vandetanib研究相似。接受vandetanib治疗的患者咳血或中枢神经系统出血的发生率并未增加，且其QT间期延长的发生率小于2%。
会上还公布了来自阿斯利康制药公司赞助的另一项小型Ⅲ期临床研究(ZEAL)的数据。ZEAL研究表明，对于先期接受过治疗的534例晚期NSCLC患者，在pemetrexed(Alimta) 治疗的基础上外加vandetanib，并不能显著改善患者的疾病无进展生存(研究的主要终点)。两者联合治疗的患者其中位疾病无进展生存期为17.6周，仅接受pemetrexed治疗者为11.9周(HR=0.86，P=0.108)。
对于抗血管生成疗法与基于紫杉醇疗法(如多西紫杉醇)联合的疗效比与其他疗法联合的疗效更佳，Edelman推测其中可能存在着某种生物学机制。临床前研究表明，紫杉醇疗法可诱导循环内皮祖细胞，后者可选择性地迁移至肿瘤中并重组其细胞构成，导致肿瘤生长加速 (Cancer Cell. 2008;14:263-73)。
“这在吉西他滨中也有所体现，人们尚未对pemetrexed进行此方面的研究，所以现在只能进行理论上的推断，”Edelman说。
两项研究均显示，vandetanib对总体生存的积极影响，但均未达统计学意义(ZODIAC中HR=0.91，P=0.196；ZEAL中HR=0.86，P=0.219)。
两项研究中，每日加用100 mg vandetanib均显著提高了肿瘤反应率(ZODIAC中17%对10%， P<0.001；ZEAL中19%对8%，P<0.001)。ZEAL研究中，患者还报告疾病相关症状的恶化延迟(HR=0.71，P=0.005)。
会上公布的由阿斯利康制药公司赞助的Ⅲ期临床试验ZEST表明，在先前治疗过的1,240例晚期NSCLC患者中，与erlotinib相比，vandetanib并未显著延长患者的疾病无进展生存期(11.3周对8.9周，HR=0.98，P=0.721)。然而，预先进行的非劣效分析发现，每日给予300 mg vandetanib与每日给予150 mg erlotinib对疾病无进展生存和总体生存率的效果相当。
在接受vandetanib或erlotinib治疗的患者中，其总体生存率、总体反应率或症状恶化时间等次要终点间相比无差异。而vandetanib组中导致死亡的不良反应发生率较高 (5.6%对2.9%)。
人们正在期待2009年下半年进行的ZEPHYR Ⅲ期临床研究的数据，此研究给予对抗EGFR治疗不敏感的局部晚期或局部转移NSCLC患者每日300 mg vandetanib加最佳支持治疗或仅给予其最佳支持治疗，并对两组进行比较。
ZODIAC研究者公开了研究的利益冲突，他们从阿斯利康制药公司获得研究基金、报酬，并为其服务或为其作顾问。他们是Genzyme公司的顾问并持有武田制药公司的股票，还从Chugai Taiho、武田、惠氏公司获得基金支持。ZEAL研究人员承认与阿斯利康公司有顾佣、顾问、持股、受薪和研究资助关系。
ZEST研究人员亦承认与阿斯利康公司有顾佣、顾问、持股、受薪和研究资助的关系。他们还从礼来、辉瑞肿瘤、罗氏公司处获得佣金，获拜耳公司的研究资助。
