【摘要】 目的按照国家食品药品监督管理局(SFDA)批复文件的要求,在国家1.1类生物新药-新型重组人血管内皮抑制素(Endostar~?,恩度~?)上市后,进一步观察和评价其联合化疗药物广泛用于临床治疗晚期非小细胞肺癌(NSCLC)患者的安全性和有效性。方法本研究为单臂、开放性、大样本、多中心的Ⅳ期临床协作研究,在全国154家大型三级甲等医院同时开展,共入组了2725例Ⅲ/Ⅳ期NSCLC患者。研究仅设立试验组,在四种常规的含铂化疗方案基础上,联合应用恩度治疗;按照药物说明书,即在化疗周期的第1～14天给予恩度(7.5 mg/m~2,静脉滴注,每天1次),连续给药14天,休息1周后继续下一个周期的治疗。主要研究终点为安全性,次要研究终点为客观有效率(ORR)、疾病控制率(DCR)、疾病进展期(TTP)和总生存期(OS)。安全性和有效性评价分别采用NCI CTC AE 3.0版和RECIST 1.0版标准。结果联合治疗的总体不良事件(AE)的发生率为94.1%,最常见的AE为白细胞减少、贫血、粒细胞减少和血小板降低,主要与采用含铂方案化疗有关,其中可能与恩度相关AE的发生率为32.6%;未观察到新的非预期的恩度相关性AE。全分析集(FAS集)中,恩度联合含铂化疗方案的ORR为20.1%,DCR为80.7%;中位TTP为7.6个月,中位OS为16.8个月,1年生存率为62.0%,2年生存率为38.3%。进一步亚组分析,初治患者、女性、肺腺癌、无远处转移和体力状况评分≥80分是预后良好的相关因素。符合方案集(PPS集)的结果与FAS集基本相似,中位TTP为7.4个月,中位OS为17.6个月,1年和2年生存率分别为63.7%和39.8%。结论本研究是在恩度上市后,联合四种常用的含铂化疗方案治疗晚期NSCLC的大样本、规范化Ⅳ期临床试验,结果数据充分表明恩度联合含铂化疗方案治疗晚期NSCLC患者的安全性良好,可以明显提高ORR和DCR,同时延长患者的TTP和OS,因此,值得在临床上进一步应用和推广。更多还原

【Abstract】 Objective According to the requirements of Chinese State of Food and Drug Administration（SFDA）, it was aim to evaluate the post-marketing safety and efficacy of an anti-tumor angiogenic biologic drug, new type recombinant human endostatin（Endostar?）, in the treatment of patients with advanced Chinese non-small cell lung cancer（NSCLC） in a large-scale. Methods The study was an open-label, large-scale, multi-center, phase IV clinical trial. It was conducted in 154 different hospitals across China, enrolling a total of 2725 patients with stage III/IV NSCLC. In the study, only the experimental group was established and Endostar was used as an add-on treatment to the conventional platinum containing chemotherapy regimen. Endostar was given continuously to the patients on d₁ to d₁₄ of the chemotherapy cycle, iv gtt once daily, 7.5 mg/m² each time and then rest for one week before they continued the next cycle of treatment. The primary endpoint was the treatment safety according NCI CTC AE 3.0 criteria, and secondary endpoint was the efficacy, including objective response rate（ORR）, disease control rate（DCR）, time to progression（TTP）, and overall survival（OS） according RECIST 1.0 criteria. Results The overall incidence of adverse events（AE） was 94.1% and the most common AE were leukopenia, anemia, neutropenia and thrombocytopenia mainly related to platinum containing chemotherapy. The incidence of possible Endostar-related AE was 32.6% and no new and unexpected AE as observed. For efficacy, the ORR was 20.1% and the DCR was 80.7%. Median OS in the full analysis set（FAS） was 16.8 months, the 1-year survival rate was 62.0%, and the 2-year survival rate was 38.3%. The median TTP was 7.6 months. Initial treatment, female, adenocarcinoma, no distant metastasis, and Karnofsky performance status>80 points were predictors of better prognosis. The results in per-protocol population set（PPS） were similar to those in FAS, with the median OS of 17.6 months, a 1-year and 2-year survival rates of 63.7% and 39.8% respectively, and a median TTP of 7.4 months. Conclusion Recombinant human endostatin（Endostar^?） combined with platinum containing chemotherapy can effectively increase ORR and DCR, prolong TTP as well as OS of patients with advanced NSCLC. The combination does not increase the incidence of chemotherapy-related adverse events. This phase IV study is the first large sample study of platinum containing combined with platinum containing chemotherapy in the treatment of advanced NSCLC, providing strong medicine evidence for the high efficacy and good safety. Thus platinum containing chemotherapies plus Endostar scheme for advanced NSCLC are the better choice and worth to be widely used in routine clinical practice.更多还原