重组人血管内皮抑素联合NP方案治疗晚期NSCLC随机、双盲、对照、多中心Ⅲ期临床研究

Results of randomized, multicenter, double-blind phase Ⅲ trial of rh-endostatin (YH-16) in treatment of advanced non-small cell lung cancer patients

背景与目的EndostarTM(YH-16)是中国烟台麦得津生物工程股份有限公司开发的新型重组人血管内皮抑素(rh-endostatin),临床前研究结果显示该药能抑制血管内皮细胞增殖、血管生成和肿瘤生长.Ⅰ、Ⅱ期临床结果证明该药单药临床应用安全有效.本研究的目的是评价YH-16联合长春瑞滨和顺铂(NP)治疗晚期非小细胞肺癌(NSCLC)的疗效和安全性.方法2003年4月～2004年6月,493例一般状况评分为0～2,经病理和细胞学确诊的Ⅲ/Ⅳ期NSCLC患者进入NP联合YH-16与NP联合安慰剂的随机、双盲、对照、多中心临床研究.研究的终点目标是有效率(RR)、临床受益率(CBR)、肿瘤进展时间(TTP)、生活质量(QOL)以及安全性.结果486例可评价疗效的患者中,试验组和对照组的总RR分别为35.4%和19.5%(P=0.0003),总CBR分别为73.3%和64.0%(P=0.035),总的中位TTP分别为6.3个月和3.6个月(P=0.0000).对初治患者,试验组和对照组的RR分别为40.0%和23.9%(P=0.003),CBR分别为76.5%和65.0%(P=0.023),中位TTP分别为6.6个月和3.7个月(P=0.0000);对复治患者,试验组和对照组的RR分别为23.9%和8.5%(P=0.034),CBR分别为65.2%和61.7%(P=0.68),中位TTP分别为5.7个月和3.2个月(P=0.0002).试验组的临床症状缓解率较对照组略高,但无统计学差异(P＞0.05).试验组与对照组疗后QOL评分比较有明显提高(P=0.0155).试验组与对照组在血液学及非血液学毒性方面,中、重度不良反应的发生率均无统计学差异.结论YH-16与NP方案联合,能明显提高晚期NSCLC的RR及中位TTP,且安全性较好,具有较好的临床应用前景.

Background and objective Endostar^TM（rh endostatin, YH-16） is a new recombinant human endostatin developed by Medgenn Bioengineering Co. Ltd. , Yantai, Shandong, P. R. China. Preclinical study indicated that YH-16 could inhibit tumor endothelial cell proliferation, angiogenesis and tumor growth. Phase Ⅰ and phase Ⅱ studies revealed that YH-16 was effective as single agent with good tolerance in clinical use. The current study was to compare the response rate, median time to progression （TTP）, clinical benefit and safety in patients with advanced non-small cell lung cancer （NSCLC）, who were treated with YH-16 plus vinorelbine and cisplatin （NP） or placebo plus NP. Methods Four hundred and ninety-three histologically or cytologically confirmed stage Ⅲ B and Ⅳ NSCLC patients, with life expectancy 〉3 months and ECOG performance status 0-2, were enrolled in a randomized, double-blind, placebo-controlled, multicenter trial, either trial group： NP plus YH-16 （vinorelbine 25 mg/m^2 on day 1 and day 5, cisplatin 30 mg/m^2 on days 2 to 4, YH-16 7.5 mg/m^2 on days 1 to 14） or control group： NP plus placebo （vinorelbine 25 mg/m^2 on day 1 and day 5, cisplatin 30 mg/m^2 on days 2 to 4, 0.9% sodium-chloride 3.75 ml on days 1 to 14） every 3 weeks for 2-6 cycles. The trial endpoints included response rate, clinical benefit rate, time to progression, quality of life and safety. Results Of 486 assessable patients, overall response rate was 35.4% in trial group and 19. 5% in control group （P=0. 0003）. The median TTP was 6.3 months and 3.6 months for trial group and control group respectively （P〈0. 001）. The clinical benefit rate was 73.3% in trial group and 64.0% in control group （P= 0.035）. In untreated patients of trial group and control group, the response rate was 40.0% and 23.9% （P= 0.003）, the clinical benefit rate was 76. 5% and 65. 0% （P=0.023）, the median TTP was 6. 6 and 3. 7 months （P=0. 0000）, respectively. In pretreated patients of trial group and control group, the response rate was 23.9% and 8.5% （P=0.034）, the clinical benefit rate was 65.2% and 61.7% （P=0.68）, the median TTP was 5.7 and 3.2 months （P=0. 0002）, respectively. The relief rate of clinical symptoms in trial group was higher than that of those in control group, but no significance existed （P〉0.05）. The score of quality of life in trial group was significantly higher than that in control group （P=0. 0155） after treatment. There were no significant differences in incidence of hematologic and non-hematologic toxicity, moderate and severe side effects between trial group and control group. Conclusion The addition of YH-16 to NP regimen results in significantly and clinically meaningful improvement in response rate, median time to tumor progression, and clinical benefit rate compared with NP alone in advanced NSCLC patients. YH-16 in combination with chemotherapy shows a synergic activity and a favorable toxic profile in advanced cancer patients.