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,The BMJ

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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
The BMJ ( IF 93.6 ) Pub Date : 2022-04-19 , DOI: 10.1136/bmj-2021-068714
Zhihao Lu ₁ , Junye Wang ₂ , Yongqian Shu ₃ , Lianke Liu ₃ , Li Kong ₄ , Lei Yang ₅ , Buhai Wang ₆ , Guogui Sun ₇ , Yinghua Ji ₈ , Guochun Cao ₉ , Hu Liu ₁₀ , Tongjian Cui ₁₁ , Na Li ₁₂ , Wensheng Qiu ₁₃ , Gaofeng Li ₁₄ , Xinfang Hou ₁₅ , Hui Luo ₁₆ , Liying Xue ₁₇ , Yanqiao Zhang ₁₈ , Wenbin Yue ₁₉ , Zheng Liu ₂₀ , Xiuwen Wang ₂₁ , Shegan Gao ₂₂ , Yueyin Pan ₂₃ , Marie-Pierre Galais ₂₄ , Aziz Zaanan ₂₅ , Zhuo Ma ₂₆ , Haoyu Li ₂₇ , Yan Wang ₂₆ , Lin Shen ₂₈ ,

Affiliation

Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China.
Department of Oncology, The Affiliated Hospital of Jining Medical College, Jining, China.
Department of Medical Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Special Needs Ward, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
Department of Medical Oncology, Nantong Tumour Hospital, Nantong, China.
Department of Medical Oncology, Northern Jiangsu People's Hospital, Affiliated Hospital to Yangzhou University, Yangzhou, China.
Department of Radiotherapy and Chemotherapy, Tangshan People's Hospital, Tangshan, China.
Department of Medical Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.
Department of Oncology, Jiangsu Cancer Hospital, Nanjing Medical University, Nanjing, China.
Department of Medical Oncology, Anhui Provincial Cancer Hospital, University of Science and Technology of China, Hefei, China.
Department of Oncology, Fujian Provincial Hospital, Fuzhou, China.
Department of Medical Oncology, Suining Central Hospital, Suining, China.
Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China.
Department of Thoracic Surgery Ward 2, Yunnan Cancer Hospital, Kunming, China.
Department of Medical Oncology, Henan Tumour Hospital, Zhengzhou, China.
Department of Thoracic Tumour Radiotherapy Ward 2, Jiangxi Cancer Hospital, Nanchang, China.
Department of Medical Oncology, Inner Mongolia People's Hospital, Hohhot, China.
Department of Digestive Oncology Ward 2, Harbin Medical University Cancer Hospital, Harbin, China.
Department of Medical Oncology, Puyang Oilfield General Hospital, Puyang, China.
Department of Medical Oncology Three, Handan Central Hospital, Handan, China.
Department of Oncology, Qilu Hospital of Shandong University, Jinan, China.
Oncology Department, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China.
Department of Tumour Chemotherapy, Anhui Provincial Hospital, Hefei, China.
Department of Medical Oncology, Centre François Baclesse, Caen, France.
Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, Paris, France.
Medical Science and Strategy Oncology, Innovent Biologics, China.
Department of Statistics, Innovent Biologics, China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China

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. Trial registration ClinicalTrials.gov [NCT03748134][1]. Reasonable requests for data sharing should be made to the corresponding author and will be handled in line with the data access and sharing policy of Human Genetic Resource Administration of China and other participating sites outside of China. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03748134&atom=%2Fbmj%2F377%2Fbmj-2021-068714.atom

更新日期：2022-04-19

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