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

Abstract

ObjectiveTo 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.DesignMulticentre, randomised, double blind, phase 3 trial.Setting66 sites in China and 13 sites outside of China between 14 December 2018 and 9 April 2021.Participants659 adults (aged ≥18 years) with advanced or metastatic oesophageal squamous cell carcinoma who had not received systemic treatment.InterventionParticipants 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 measuresOverall survival in all patients and in patients with combined positive scores of ≥10 for expression of programmed cell death ligand 1.Results659 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.ConclusionsCompared 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 registrationClinicalTrials.gov NCT03748134.

Real-World Efficacy and Safety of Sintilimab-Based Regimens against Advanced Esophageal Cancer: A Single-Center Retrospective Observational Study

“…In the ORIENT-15 trial, 659 patients were randomly divided into sintilimab combined with chemotherapy and placebo combined with chemotherapy. The ORR and median OS of the sintilimab group were better than those of the placebo group (66.1% vs. 45.5%, 16.7 months vs. 12.5 months) [ 26 ]. The ORR of all populations in this study was 60%, which was lower than 66.1% of ORIENT-15.…”

“…ORIENT-15 trial showed that grade 1-2 treatment-related AEs of sintilimab combined with chemotherapy were mainly anemia, decrease in white blood cell count, nausea, and vomiting. The most common grade 3-4 AEs were neutropenia, leukopenia, and anemia [ 26 ]. Treatment-related AEs in this study were similar to ORIENT-15 results, except for the incidence of pneumonia.…”

Chemoimmunotherapy in advanced esophageal squamous cell carcinoma: optimizing chemotherapy regimens for immunotherapy combinations

“…A recent study published in BMJ by Lu et al 1 has reported the interim findings from the ORIENT-15, which is a global, multi-center and randomized phase 3 trial to compare chemoimmunotherapy to chemotherapy alone as first-line treatment in advanced esophageal squamous cell carcinoma (ESCC), and provoked thinking about the chemotherapy regimens for chemoimmunotherapy combinations.…”

“…Immune-checkpoint blockades (ICB) have been added to chemotherapy in advanced esophageal cancers in multiple clinical trials. The KEYNOTE-590 (pembrolizumab), ESCORT-1st (camrelizumab), CheckMate-648 (nivolumab), JUPITER-6 (toripalimab), and ORIENT-15 (sintilimab) 1 trials all showed superior response and survival for chemoimmunotherapy. These results provided solid evidence for chemoimmunotherapy as first-line treatment of advanced ESCC.…”

“…Similarly, for progression-free survival, ICB + PC seemed to have relatively more combination benefit compared with ICB + CF. For the current studies, only ORIENT-15 study 1 was designed with stratification of chemotherapy regimens and results showed that HR for OS of ICB + PC vs. PC and ICB + CF vs. CF were 0.65 and 0.31, respectively. Of note, the HR of ICB + CF subgroup was not statistically significant, which may be due to the small number of patients (7% of total).…”