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Clinical Trial
. 2022 Apr 19:377:e068714.
doi: 10.1136/bmj-2021-068714.

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

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 ; ORIENT-15 study group
Collaborators, Affiliations
Clinical Trial

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

Zhihao Lu et al. BMJ. .

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.

Trial registration: ClinicalTrials.gov NCT03748134.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from Innovent Biologics and Eli Lilly for the submitted work; LS reports receiving research funding from Innovent Biologics, Beijing Xiantong Biomedical Technology, Qilu Pharmaceutical, ZaiLab Pharmaceutical, Beihai Kangcheng (Beijing) Medical Technology, and Jacobio Pharmaceuticals; consultant fees from MSD, Merck, Mingji Biopharmaceutical, Haichuang Pharmaceutical, Herbour Biomed, and BI; honoraria from Hutchison Whampoa, Hengrui, ZaiLab, and CSTONE pharmaceutical; and serving as a consultant for Rongchang Pharmaceutical, ZaiLab, CSTONE Pharmaceutical, and BMS. AZ has participated in consulting boards, advisory boards, or both, for Amgen, Lilly, Merck, Roche, Sanofi, Servier, Baxter, MSD, Pierre Fabre, Havas Life, Alira Health, and Zymeworks.

Figures

Fig 1
Fig 1
Flowchart of trial design. *Positive for surface antigen of hepatitis B virus and hepatitis B virus DNA viral load ≥103 copies/mL or ≥200 IU/mL, or acute or chronic active hepatitis C (positive hepatitis C virus antibody and positive hepatitis C virus RNA). †Table S3 lists details of other reasons. ‡Tumour lesion of liver at baseline was confirmed as primary hepatocellular carcinoma after study treatment. §Other reasons included start of new antitumour treatment and non-compliance with protocol. ECOG PS=Eastern Cooperative Oncology Group performance status score
Fig 2
Fig 2
Overall survival in patients who received sintilimab or placebo in combination with chemotherapy. Kaplan-Meier plot of overall survival in all patients (top) and in patients with combined positive scores of ≥10 for expression of programmed cell death ligand 1 (bottom). Values for overall survival are median (95% confidence interval) and hazard ratio (95% confidence interval). P values are two sided. NC=not calculated
Fig 3
Fig 3
Forest plot for subgroup analyses of overall survival in patients who received sintilimab or placebo in combination with chemotherapy. ECOG PS=Eastern Cooperative Oncology Group performance status score; PD-L1, programmed cell death ligand 1; TPS=tumour proportion score; CPS=combined positive score; NC=not calculated
Fig 4
Fig 4
Progression free survival in patients who received sintilimab or placebo in combination with chemotherapy. Kaplan-Meier plot of progression free survival in all patients (top) and in patients with combined positive scores of ≥10 for expression of programmed cell death ligand 1 (bottom). Values for progression free survival are median (95% confidence interval) and hazard ratio (95% confidence interval). P values are two sided
Fig 5
Fig 5
Forest plot for subgroup analyses of progression free survival in patients who received sintilimab or placebo in combination with chemotherapy. ECOG PS=Eastern Cooperative Oncology Group performance status score; PD-L1, programmed cell death ligand 1; TPS=tumour proportion score; CPS=combined positive score; NC=not calculated
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