Results of a pivotal phase III trial that led to approval of pemetrexed as the first maintenance therapy in locally advanced or metastatic nonsquamous non–small cell lung cancer are being published online Sept. 19 by the Lancet.
Pemetrexed maintenance improved median overall survival by 2.8 months and median progression-free survival by 1.7 months in the placebo-controlled, 663-patient trial, according to the paper by lead author Dr. Tudor Ciuleanu of the Cancer Institute Ion Chiricuta, Cluj-Napoca, Romania, and his coinvestigators in the 20-country study (Lancet 2009 Sept. 19 [doi:10.1016/S0140-6736(09)61497-5]).
An accompanying comment by two oncologists says the strategy “merits being considered as a strong option,” as reflected by the approvals of maintenance pemetrexed in the United States and Europe. The authors of the comment raise questions about the poststudy treatment of patients who progressed, however, and call for caution in interpreting the results (Lancet 2009 Sept. 19 [doi:10.1016/S0140-6736(09)61598-1]).
“We cannot assume that the survival benefit observed in today’s trial is entirely a function of the timing of maintenance therapy,” explain Dr. Thomas E. Stinchcombe of the University of North Carolina at Chapel Hill and Dr. Howard L. West of the Swedish Cancer Institute in Seattle.
Eli Lilly and Co. sponsored the trial, which was conducted at 83 centers. The principal investigator, Dr. Chandra P. Belani of Penn State Cancer Institute in Hershey, Pennsylvania., presented the results earlier this year at the American Society of Clinical Oncology’s annual meeting.
Starting in March 2005, investigators enrolled 745 adult patients with advanced stage IIIB or IV non–small cell lung cancer (NSCLC) that had not progressed during four cycles of platinum-based chemotherapies. After exclusions of 82 patients, mostly for not meeting study criteria, 663 patients were randomized on a 2:1 basis (441 to pemetrexed and 222 to placebo).
Pemetrexed was delivered intravenously at 500 mg/m2 on day 1 of 21-day cycles until disease progression. Both study arms also received best supportive care. Intent-to-treat analyses were based on all 663 patients at a median follow-up from randomization of 11.2 months.
Median progression-free survival, the primary end point, lasted significantly longer in the pemetrexed arm than the placebo arm (4.3 months vs. 2.6 months, respectively; hazard ratio, 0.50; P = less than .0001) by investigator assessment. The improvement in median overall survival also favored pemetrexed significantly (13.4 months vs. 10.6 months; HR, 0.79; P = .12). Response and disease-control rates were reported to be better in the pemetrexed arm as well.
An independent review of scans from 581 patients produced slightly shorter survival advantages, but the differences remained statistically significant, according to the report. As with previous pemetrexed trials, the benefits were observed mainly in patients with nonsquamous histology.
Although grade 3 or higher adverse events were more common with pemetrexed (16% vs. 4%), as were drug-related discontinuations (5% vs. 1%), the investigators found the drug to be well tolerated and not the cause of any treatment-related deaths.
What concerned Dr. Stinchcombe and Dr. West in their comment was a “striking difference” in the treatments that patients in the two arms of the trial received after disease progression. Just over half of the pemetrexed group (227 patients, or 51%) received systemic therapy vs. about two-thirds of the placebo arm (149 patients, or 67%). The treatments were at the choice of the investigator, and only 41 patients (18%) of the placebo arm crossed over to pemetrexed.
The trial investigators concluded that poststudy therapy probably did not affect survival results “in view of the higher rate of follow-up treatment in the placebo group than in the pemetrexed group, low rate of crossover, and the balanced selection of therapies between groups.”
Dr. Stinchcombe and Dr. West were not so sure. They noted that about a third of the control arm had a period of stable disease, whereas 40% of those given maintenance pemetrexed had disease progression and possible side effects from the treatment. Until the timing of maintenance therapy can be dissociated from differences in access to effective second-line therapies, they suggested the following:
“For patients who have a response or stable disease with first-line chemotherapy, who tolerated platinum-based therapy without limiting toxicity while maintaining a good performance status, and who desire to continue therapy, maintenance therapy is an appealing consideration. However, if patients have had substantial toxicity with first-line therapy or desire a treatment-free interval, close monitoring and starting timely second-line therapy at disease progression remains an appropriate alternative.”
Some trial investigators, including Dr. Ciuleanu and Dr. Belani, disclosed relationships with Eli Lilly; four of the study authors were company employees with stock ownership. Dr. Stinchcombe and Dr. West disclosed serving on the speakers bureau of Lilly Oncology.
See video interview at http://www.youtube.com/watch?v=9S_-jhW_FoE.
Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
《柳叶刀》( The Lancet ) 9月19日在线发表的一项关键性III期临床试验的研究结果表明，培美曲塞(pemetrexed)作为首个维持治疗局部晚期或转移性非鳞状细胞性非小细胞肺癌药物获得认可。
该研究在20个国家展开，文章的主要作者罗马尼亚克鲁日-纳波卡市Ion Chiricuta肿瘤研究所的Tudor Ciuleanu博士及其同事指出：试验共纳入663例患者，与安慰剂对照组相比，培美曲塞(商品名：力比泰)维持治疗组的患者总体中位生存时间延长 2.8个月，中位无进展生存时间延长1.7个月(Lancet 2009 Sept. 19 [doi:10.1016/S0140-6736(09)61497-5])。
在随刊评论中，两位肿瘤学家说该治疗策略“优势很大，可考虑作为备选方案”，这在美国和欧洲批准培美曲塞用于维持治疗上也得到了印证。但评论作者也提出了关于进展患者试验后续治疗的问题，并呼吁对试验结果的解释仍需保持谨慎(Lancet 2009 Sept. 19 [doi:10.1016/S0140-6736(09)61598-1])。
美国北卡罗莱纳大学教堂山分校Thomas E. Stinchcombe博士和西雅图市Swedish癌症研究所Howard L. West博士解释说：“我们并不能断定在该试验所观察到的生存优势完全是培美曲塞维持治疗在起作用。”
该试验在83个临床中心展开，礼来公司为其提供了资助。宾夕法尼亚州Hershey州立癌症研究所的Chandra P. Belani博士是主要研究人员，他在年初的美国临床肿瘤学会年会上发表了上述结果。
研究于2005年3月份启动，共募集745例晚期（IIIB期或IV期）非小细胞肺癌(NSCLC)成年患者，此前均经过4个周期的铂类药物为主的化疗，且无疾病进展。82例患者主要因不符合研究标准而被排除，其余663例患者按2:1随机进行分组(培美曲塞组441例，安慰剂组222例)。
培美曲塞经静脉给药，第1天500 mg/m2，21天为1个化疗周期，直至疾病进展。两组受试者均接受了最佳支持治疗。在中位时间为11.2个月的随访中，对所有663例患者随机进行了意向性治疗分析。
与对照组相比，培美曲塞组的中位无进展生存时间(研究的主要终点)显著延长，分别为4.3个月和 2.6个月(风险比为0.50，P<0.0001)。同时，培美曲塞组的总体中位生存时间显著增加，分别为13.4个月和10.6个月(风险比为0.79，P=0.12)。此外，治疗组的缓解率和疾病控制率也优于对照组。
根据该报告，一份纳入581例患者的独立回顾性分析发现培美曲塞治疗患者具有时间稍短的生存优势，但与对照组相比，仍然存在显著性差异。而根据以往的培美曲塞试验，主要是组织学为非鳞状上皮的肺癌患者才具有这种生存优势。
尽管培美曲塞组较常出现3级或3级以上不良事件(16%比4%)以及药物相关性撤药事件(5%比1%)，但研究人员发现培美曲塞是一种耐受性良好的药物，且不会导致任何与治疗相关的死亡。
Stinchcombe博士和West博士在评论中指出，他们所关心的是两组患者在疾病进展后接受治疗的“显著差异”。培美曲塞组恰好超过半数的患者(227例，51%)接受了全身性治疗，安慰剂组则占到2/3(149例，67%)。由研究者判断患者是否需要接受治疗，仅有41例(18%)安慰剂组患者改用培美曲塞治疗。
研究人员在结论中写道，“鉴于安慰剂组后续治疗率比培美曲塞组更高以及两组间跨组患者少、治疗患者的选择比较均衡，”试验后续治疗可能并不会影响生存期结果。
Stinchcombe博士和West博士对此并不十分确定。他们指出，对照组约1/3的患者病情稳定，而接受培美曲塞维持治疗的患者中有40%出现疾病进展以及治疗相关的副作用。除非维持治疗在时机选择上能摒除有效的二线治疗的差异影响，他们建议这样做：
“对于一线化疗后病情缓解或稳定者、要求继续治疗者以及能耐受铂类药物为主的化疗且当维持较好疗效剂量下未发生限制性毒性的患者，培美曲塞维持治疗都是一种极好的选择。但如果患者已经发生一线化疗引起的实质性毒性反应或要求化疗期间不进行治疗，则密切监视病情并在疾病进展时及时启动二线治疗仍然是合适的替代方案。”
部分研究人员称与礼来公司存在利益关系，其中包括Ciuleanu博士和Belani博士。有4名研究者是礼来公司雇员，持有公司股票。Stinchcombe博士和West博士是礼来肿瘤部的讲师团成员。
观看采访视频请访问：http://www.youtube.com/watch?v=9S_-jhW_FoE。
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