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

Introduction Extensive-stage small cell lung cancer (ES-SCLC) prognosis remains poor. The phase 3 RATIONALE-312 study aimed to evaluate 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 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 endpoint was overall survival (OS). Secondary endpoints included progression free-survival (PFS) 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 data cutoff (April 19, 2023), median study follow-up was 14.2 months (IQR: 8.6–25.3). Tislelizumab plus chemotherapy demonstrated a statistically significant OS benefit versus placebo plus chemotherapy (stratified HR=0.75 [95% CI: 0.61–0.93]; one-sided p=0.0040; median: 15.5 [95% CI: 13.5–17.1] versus 13.5 months [95% CI: 12.1–14.9], respectively). PFS was significantly improved in the tislelizumab versus placebo arm (stratified HR=0.64 [95% CI: 0.52–0.78]; p<0.0001; median: 4.7 [95% CI: 4.3–5.5] versus 4.3 months [95% CI: 4.2–4.4], respectively). Grade ≥3 treatment-related adverse events were reported in 86% of patients in each treatment arm and were mostly hematological. Conclusion Tislelizumab plus chemotherapy demonstrated statistically significant clinical benefit and manageable safety compared with placebo plus chemotherapy as first-line treatment in patients with advanced ES-SCLC.