北京大学肿瘤医院沈琳教授团队比较了信迪利单抗与安慰剂联合化疗作为局部晚期或转移性食管鳞癌一线治疗的效果。这一研究成果于2022年4月19日发表在《英国医学杂志》上。
为了评估信迪利单抗与安慰剂联合化疗（顺铂+紫杉醇或顺铂+5-氟尿嘧啶）作为无法切除的局部晚期、复发或转移性食管鳞癌的一线治疗的效果，2018年12月14日至2021年4月9日，研究组在中国境内66个机构和境外13个机构进行了一项多中心、随机、双盲、3期临床试验。共招募了659名年龄≥18岁、患有晚期或转移性食管鳞状细胞癌、未接受系统治疗的参与者。
将参与者按1:1的比例随机分组，分别接受每3周一次信迪利单抗或安慰剂，同时联合顺铂75mg/m2加紫杉醇175mg/m2的治疗。对该试验进行改良，允许研究人员选择化疗方案：顺铂+紫杉醇或顺铂+5-氟尿嘧啶（第1-5天持续输注800 mg/m2）。主要观察指标为所有患者的总生存期，以及程序性细胞死亡配体1表达综合阳性评分≥10的患者的总生存期。
659例患者被随机分为两组，其中信迪利单抗组327例，安慰剂组332例。659名患者中有616名（93%）接受了信迪利单抗或安慰剂联合顺铂+紫杉醇治疗，43名（7%）接受了信迪利单抗或安慰剂联合顺铂+5-氟尿嘧啶治疗。在中期分析中，在所有患者中，信迪利单抗组的中位总生存期为16.7个月，显著长于安慰剂组的12.5个月；在PD-L1综合阳性评分≥10的患者中，信迪利单抗组的中位总生存期为17.2个月，显著长于安慰剂组的13.6个月。
在所有患者中，信迪利单抗组的中位无进展生存期为7.2个月，显著长于安慰剂组的5.7个月；在PD-L1综合阳性评分≥10的患者中，信迪利单抗组的中位无进展生存期为8.3个月，显著长于安慰剂组的6.4个月。信迪利单抗组327名患者中有321名（98%）发生与治疗相关的不良事件，安慰剂组332名患者中有326名（98%）；两组分别有60%和55%的患者发生≥3级的与治疗、分级有关的不良事件。
研究结果表明，与安慰剂相比，信迪利单抗联合顺铂和紫杉醇作为晚期或转移性食管鳞癌患者的一线治疗，在总生存期和无进展生存期方面显示出显著优势。信迪利单抗与顺铂加5-氟尿嘧啶的类似临床益处似乎也颇有潜力。
附：英文原文
Title: Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (ORIENT-15): multicentre, randomised, double blind, phase 3 trial
Author: Zhihao Lu, Junye Wang, Yongqian Shu, Lianke Liu, Li Kong, Lei Yang, Buhai Wang, Guogui Sun, Yinghua Ji, Guochun Cao, Hu Liu, Tongjian Cui, Na Li, Wensheng Qiu, Gaofeng Li, Xinfang Hou, Hui Luo, Liying Xue, Yanqiao Zhang, Wenbin Yue, Zheng Liu, Xiuwen Wang, Shegan Gao, Yueyin Pan, Marie-Pierre Galais, Aziz Zaanan, Zhuo Ma, Haoyu Li, Yan Wang, Lin Shen
Issue&Volume: 2022/04/19
Abstract:
Objective To evaluate sintilimab versus placebo in combination with chemotherapy (cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil) as first line treatment of unresectable locally advanced, recurrent, or metastatic oesophageal squamous cell carcinoma.
Design Multicentre, randomised, double blind, phase 3 trial.
Setting 66 sites in China and 13 sites outside of China between 14 December 2018 and 9 April 2021.
Participants 659 adults (aged ≥18 years) with advanced or metastatic oesophageal squamous cell carcinoma who had not received systemic treatment.
Intervention Participants were randomised 1:1 to receive sintilimab or placebo (3 mg/kg in patients weighing <60 kg or 200 mg in patients weighing ≥60 kg) in combination with cisplatin 75 mg/m2 plus paclitaxel 175 mg/m2 every three weeks. The trial was amended to allow investigators to choose the chemotherapy regimen: cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil (800 mg/m2 continuous infusion on days 1-5).
Main outcome measures Overall survival in all patients and in patients with combined positive scores of ≥10 for expression of programmed cell death ligand 1.
Results 659 patients were randomly assigned to sintilimab (n=327) or placebo (n=332) with chemotherapy. 616 of 659 patients (93%) received sintilimab or placebo in combination with cisplatin plus paclitaxel and 43 of 659 patients (7%) received sintilimab or placebo in combination with cisplatin plus 5-fluorouracil. At the interim analysis, sintilimab with chemotherapy showed better overall survival compared with placebo and chemotherapy in all patients (median 16.7 v 12.5 months, hazard ratio 0.63, 95% confidence interval 0.51 to 0.78, P<0.001) and in patients with combined positive scores of ≥10 (17.2 v 13.6 months, 0.64, 0.48 to 0.85, P=0.002). Sintilimab and chemotherapy significantly improved progression free survival compared with placebo and chemotherapy in all patients (7.2 v 5.7 months, 0.56, 0.46 to 0.68, P<0.001) and in patients with combined positive scores of ≥10 (8.3 v 6.4 months, 0.58, 0.45 to 0.75, P<0.001). Adverse events related to treatment occurred in 321 of 327 patients (98%) in the sintilimab-chemotherapy group versus 326 of 332 (98%) patients in the placebo-chemotherapy group. Rates of adverse events related to treatment, grade ≥3, were 60% (196/327) and 55% (181/332) in the sintilimab-chemotherapy and placebo-chemotherapy groups, respectively.
Conclusions Compared with placebo, sintilimab in combination with cisplatin plus paclitaxel showed significant benefits in overall survival and progression free survival as first line treatment in patients with advanced or metastatic oesophageal squamous cell carcinoma. Similar benefits of sintilimab with cisplatin plus 5-fluorouracil seem promising.
DOI: 10.1136/bmj-2021-068714
Source: https://www.bmj.com/content/377/bmj-2021-068714
BMJ-British Medical Journal:《英国医学杂志》，创刊于1840年。隶属于BMJ出版集团，最新IF：93.333
官方网址：http://www.bmj.com/
投稿链接：https://mc.manuscriptcentral.com/bmj
本期文章：《英国医学杂志》：Online/在线发表
