Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China.
Department of Oncology, The Affiliated Hospital of Jining Medical College, Jining, China.
BMJ. 2022 Apr 19;377:e068714. doi: 10.1136/bmj-2021-068714.
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.
Multicentre, randomised, double blind, phase 3 trial.
66 sites in China and 13 sites outside of China between 14 December 2018 and 9 April 2021.
659 adults (aged ≥18 years) with advanced or metastatic oesophageal squamous cell carcinoma who had not received systemic treatment.
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/m plus paclitaxel 175 mg/m 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/m continuous infusion on days 1-5).
Overall survival in all patients and in patients with combined positive scores of ≥10 for expression of programmed cell death ligand 1.
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 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 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 5.7 months, 0.56, 0.46 to 0.68, P<0.001) and in patients with combined positive scores of ≥10 (8.3 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.
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.
ClinicalTrials.gov NCT03748134.
评价信迪利单抗联合化疗（顺铂+紫杉醇或顺铂+氟尿嘧啶）作为不可切除的局部晚期、复发性或转移性食管鳞状细胞癌的一线治疗药物。
多中心、随机、双盲、Ⅲ期临床试验。
中国 66 个地点和中国以外的 13 个地点，时间为 2018 年 12 月 14 日至 2021 年 4 月 9 日。
659 名年龄≥18 岁的晚期或转移性食管鳞状细胞癌患者，且未接受过系统治疗。
参与者以 1:1 的比例随机接受信迪利单抗或安慰剂（体重<60kg 者给予 3mg/kg，体重≥60kg 者给予 200mg）联合顺铂 75mg/m2 加紫杉醇 175mg/m2，每 3 周一次。试验进行了修订，允许研究者选择化疗方案：顺铂+紫杉醇或顺铂+氟尿嘧啶（第 1-5 天连续输注 800mg/m2）。
所有患者和程序性死亡配体 1 表达综合阳性评分≥10 的患者的总生存期。
659 例患者随机分为信迪利单抗（n=327）或安慰剂（n=332）联合化疗。659 例患者中，616 例（93%）接受了信迪利单抗或安慰剂联合顺铂+紫杉醇治疗，43 例（7%）接受了信迪利单抗或安慰剂联合顺铂+氟尿嘧啶治疗。在中期分析中，与安慰剂和化疗相比，信迪利单抗联合化疗在所有患者（中位总生存期 16.7 比 12.5 个月，风险比 0.63，95%置信区间 0.51 至 0.78，P<0.001）和综合阳性评分≥10 的患者（17.2 比 13.6 个月，0.64，0.48 至 0.85，P=0.002）中均显示出更好的总生存期。与安慰剂和化疗相比，信迪利单抗联合化疗在所有患者（无进展生存期 7.2 比 5.7 个月，0.56，0.46 至 0.68，P<0.001）和综合阳性评分≥10 的患者（8.3 比 6.4 个月，0.58，0.45 至 0.75，P<0.001）中均显著改善了无进展生存期。327 例信迪利单抗-化疗组患者（98%）和 332 例安慰剂-化疗组患者（98%）中，有 321 例（98%）发生与治疗相关的不良事件。与治疗相关的不良事件发生率为 60%（196/327）和 55%（181/332），分别为信迪利单抗-化疗组和安慰剂-化疗组。
与安慰剂相比，信迪利单抗联合顺铂+紫杉醇作为晚期或转移性食管鳞状细胞癌的一线治疗药物，在总生存期和无进展生存期方面具有显著获益。信迪利单抗联合顺铂+氟尿嘧啶的获益似乎也很有前景。
ClinicalTrials.gov NCT03748134。
