安慰剂联合化疗治疗局部晚期或转移性食管鳞癌的一线治疗

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

（Clinical Trial IF:39.890）

Objective 目的

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.

评价sintilimab与安慰剂联合化疗(顺铂+紫杉醇或顺铂+5-氟尿嘧啶)治疗不能切除的局部晚期、复发或转移性食管鳞癌的一线疗效。

Design 设计

Multicentre, randomised, double blind, phase 3 trial.

多中心、随机、双盲。第三阶段试验。

Setting 地点

 66 sites in China and 13 sites outside of China between 14 December 2018 and 9 April 2021.

2018年12月14日至2021年4月9日，中国境内66个地点，境外13个地点。

Participants 参与者

659 adults (aged ≥18 years) with advanced or metastatic oesophageal squamous cell carcinoma who had not received systemic treatment.

659例未接受系统治疗的晚期或转移性食管鳞癌患者(年龄18岁，≥)。

Intervention 干预

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).

参与者以1：1的随机比例接受sintilimab或安慰剂(体重<60 kg的患者为3 mg/kg，体重为≥60 kg的患者为200 mg/kg)联合顺铂75 mg/m2加紫杉醇175 mg/m2，每三周一次。对试验进行修改，以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(800 mg/m2持续滴注，第1~5天)。

Main outcome measures 主要观察指标

Overall survival in all patients and in patients with combined positive scores of ≥10 for expression of programmed cell death ligand 1.

所有患者和≥10表达编程细胞死亡配体1综合阳性的患者的总生存期。

Results 结果

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.

659例患者随机分为sintilimab组和安慰剂组。659例患者中616例(93%)接受sintilimab或安慰剂联合顺铂+紫杉醇治疗，659例患者中43例(7%)接受sintilimab或安慰剂联合顺铂+5-氟尿嘧啶治疗。在中期分析中，sintilimab联合化疗的总生存率(中位数16.7vs12.5个月，风险比0.63，95%可信区间0.51~0.78，P<0.001)和≥10综合阳性评分的患者(17.2v13.6个月，0.64，0.48~0.85，P=0.002)。与安慰剂和化疗组比较，sintilimab联合化疗可显著提高患者的无进展生存期(7.2月比5.7月，0.56月，0.46~0.68，P<0.001)，≥-10综合评分阳性患者的无进展生存期(8.3vs6.4月，0.58月，0.45~0.75，P<0.001)。与治疗相关的不良事件，辛替利马化疗组327名患者中有321名(98%)，而安慰剂化疗组332名患者中有326名(98%)。sintilimab化疗组和安慰剂化疗组≥3级不良反应发生率分别为60%(196/32)和55%(181/332)。

Conclusions 结论

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.

sintilimab联合顺铂加紫杉醇治疗晚期或转移性食管鳞癌，与安慰剂相比，总体生存期和无进展生存期均有显著改善。sintilimab联合顺铂和5-氟尿嘧啶的类似疗效似乎是有希望的。

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