Tislelizumab Plus Platinum and Etoposide Versus Placebo Plus Platinum and Etoposide as First-Line Treatment for Extensive-Stage SCLC (RATIONALE-312): A Multicenter, Double-Blind, Placebo-Controlled, Randomized, Phase 3 Clinical Trial

Ying Cheng; Yun Fan; Yanqiu Zhao; Dingzhi Huang; Xingya Li; Peng Zhang; Mafei Kang; Nong Yang; Diansheng Zhong; Zhen Wang; Yan Yu; Yu Zhang; Jun Zhao; Tai Qin; Chenqi Chen; Shiangjiin Leaw; Wenjuan Zheng; Yong Song; RATIONALE-312 Study Group

doi:10.1016/j.jtho.2024.03.008

Tislelizumab Plus Platinum and Etoposide Versus Placebo Plus Platinum and Etoposide as First-Line Treatment for Extensive-Stage SCLC (RATIONALE-312): A Multicenter, Double-Blind, Placebo-Controlled, Randomized, Phase 3 Clinical Trial

J Thorac Oncol. 2024 Mar 7:S1556-0864(24)00115-1. doi: 10.1016/j.jtho.2024.03.008. Online ahead of print.

Authors

Ying Cheng¹, Yun Fan², Yanqiu Zhao³, Dingzhi Huang⁴, Xingya Li⁵, Peng Zhang⁶, Mafei Kang⁷, Nong Yang⁸, Diansheng Zhong⁹, Zhen Wang¹⁰, Yan Yu¹¹, Yu Zhang¹², Jun Zhao¹³, Tai Qin¹⁴, Chenqi Chen¹⁵, Shiangjiin Leaw¹⁵, Wenjuan Zheng¹⁴, Yong Song¹⁶; RATIONALE-312 Study Group

Affiliations

¹ Department of Thoracic Oncology, Jilin Cancer Hospital, Changchun, People's Republic of China. Electronic address: jl.cheng@163.com.
² Department of Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, People's Republic of China.
³ Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, People's Republic of China.
⁴ Pulmonary Oncology Department, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China.
⁵ Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China.
⁶ Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
⁷ Department of Medical Oncology, The Affiliated Hospital of Guilin Medical University, Guilin, People's Republic of China.
⁸ Lung Cancer and Gastrointestinal Unit, Department of Medical Oncology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, People's Republic of China.
⁹ Department of Medical Oncology, Tianjin Medical University General Hospital, Tianjin, People's Republic of China.
¹⁰ Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, People's Republic of China.
¹¹ Harbin Medical University Cancer Hospital, Harbin, People's Republic of China.
¹² Department of Respiratory Medicine, Nanjing Chest Hospital, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, People's Republic of China.
¹³ Department of Thoracic Oncology, Beijing Cancer Hospital, Beijing, People's Republic of China.
¹⁴ Clinical Development, Solid Tumors, BeiGene (Beijing) Co., Ltd., Beijing, People's Republic of China.
¹⁵ Statistics, BeiGene (Shanghai) Co., Ltd., Shanghai, People's Republic of China.
¹⁶ Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, People's Republic of China.

PMID: 38460751
DOI: 10.1016/j.jtho.2024.03.008

Abstract

Introduction: Extensive-stage SCLC (ES-SCLC) prognosis remains poor. The phase 3 RATIONALE-312 study aimed to evaluate the efficacy and safety of tislelizumab plus chemotherapy as first-line treatment for ES-SCLC.

Methods: RATIONALE-312 is a randomized, double-blind, placebo-controlled trial, conducted in the People's Republic of China. Eligible patients with previously untreated ES-SCLC were randomized 1:1 to receive four cycles of tislelizumab 200 mg or placebo, with etoposide plus carboplatin or cisplatin intravenously every 3 weeks, followed by tislelizumab 200 mg or placebo as maintenance. The primary end point was overall survival (OS). Secondary end points included progression-free survival and safety.

Results: Between July 22, 2019 and April 21, 2021, 457 patients were randomized to tislelizumab (n = 227) or placebo (n = 230), plus chemotherapy. Baseline demographics were generally balanced between arms. At the data cutoff (April 19, 2023), the median study follow-up was 14.2 months (interquartile range: 8.6-25.3). Tislelizumab plus chemotherapy exhibited a statistically significant OS benefit versus placebo plus chemotherapy (stratified hazard ratio = 0.75 [95% confidence interval (CI): 0.61-0.93]; one-sided p = 0.0040; median: 15.5 [95% CI: 13.5-17.1] versus 13.5 mo [95% CI: 12.1-14.9], respectively). Progression-free survival was significantly improved in the tislelizumab versus placebo arm (stratified hazard ratio = 0.64 [95% CI: 0.52-0.78]; p < 0.0001; median: 4.7 [95% CI: 4.3-5.5] versus 4.3 mo [95% CI: 4.2-4.4], respectively). Grade greater than or equal to 3 treatment-related adverse events were reported in 86% of patients in each treatment arm and were mostly hematologic.

Conclusions: Tislelizumab plus chemotherapy exhibited statistically significant clinical benefit and manageable safety compared with placebo plus chemotherapy as first-line treatment in patients with advanced ES-SCLC.

Keywords: Extensive-stage SCLC; Immunotherapy; PD-1; Tislelizumab.