Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study

• Published in: The lancet oncology 2023-05, Vol.24 (5), p.483-495
• Main Authors: Xu, Jianming, Kato, Ken, Raymond, Eric, Hubner, Richard A, Shu, Yongqian, Pan, Yueyin, Park, Sook Ryun, Ping, Lu, Jiang, Yi, Zhang, Jingdong, Wu, Xiaohong, Yao, Yuanhu, Shen, Lin, Kojima, Takashi, Gotovkin, Evgeny, Ishihara, Ryu, Wyrwicz, Lucjan, Van Cutsem, Eric, Jimenez-Fonseca, Paula, Lin, Chen-Yuan, Wang, Lei, Shi, Jingwen, Li, Liyun, Yoon, Harry H
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Adolescent; Adult; Adverse events; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Cancer therapies; Chemotherapy; Cisplatin; Clinical medicine; Cytotoxicity; Disease; Double-Blind Method; Esophageal cancer; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagus; Female; Heart diseases; Hemorrhage; Humans; Leukocytes (neutrophilic); Male; Medical practices; Medical prognosis; Metastases; Metastasis; Middle Aged; Monoclonal antibodies; Myocarditis; Oxaliplatin; Paclitaxel; Patients; PD-1 protein; PD-L1 protein; Placebos; Respiratory failure; Septic shock; Solid tumors; Squamous cell carcinoma; Survival analysis; Targeted cancer therapy; Toxicity; Tumors
• ISSN: 1470-2045; 1474-5488
• DOI: 10.1016/S1470-2045(23)00108-0

The options for first-line treatment of advanced oesophageal squamous cell carcinoma are scarce, and the outcomes remain poor. The anti-PD-1 antibody, tislelizumab, has shown antitumour activity in previously treated patients with advanced oesophageal squamous cell carcinoma. We report interim analysis results from the RATIONALE-306 study, which aimed to assess tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma. This global, randomised, double-blind, parallel-arm, placebo-controlled, phase 3 study was conducted at 162 medical centres across Asia, Europe, Oceania, and North America. Patients (aged ≥18 years) with unresectable, locally advanced, recurrent or metastatic oesophageal squamous cell carcinoma (regardless of PD-L1 expression), Eastern Cooperative Oncology Group performance status of 0–1, and measurable or evaluable disease per Response Evaluation Criteria in Solid Tumours (version 1.1) were recruited. Patients were randomly assigned (1:1), using permuted block randomisation (block size of four) and stratified by investigator-chosen chemotherapy, region, and previous definitive therapy, to tislelizumab 200 mg or placebo intravenously every 3 weeks on day 1, together with an investigator-chosen chemotherapy doublet, comprising a platinum agent (cisplatin 60–80 mg/m2 intravenously on day 1 or oxaliplatin 130 mg/m2 intravenously on day 1) plus a fluoropyrimidine (fluorouracil [750–800 mg/m2 intravenously on days 1–5] or capecitabine [1000 mg/m2 orally twice daily on days 1–14]) or paclitaxel (175 mg/m2 intravenously on day 1). Treatment was continued until disease progression or unacceptable toxicity. Investigators, patients, and sponsor staff or designees were masked to treatment. The primary endpoint was overall survival. The efficacy analysis was done in the intention-to-treat population (ie, all randomly assigned patients) and safety was assessed in all patients who received at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, NCT03783442. Between Dec 12, 2018, and Nov 24, 2020, 869 patients were screened, of whom 649 were randomly assigned to tislelizumab plus chemotherapy (n=326) or placebo plus chemotherapy (n=323). Median age was 64·0 years (IQR 59·0–69·0), 563 (87%) of 649 participants were male, 86 (13%) were female, 486 (75%) were Asian, and 155 (24%) were White. 324 (99%) of 326 patients in the tislelizumab