RATIONALE-306: Randomized, global, placebo-controlled, double-blind phase 3 study of tislelizumab plus chemotherapy versus chemotherapy as first-line treatment for advanced or metastatic esophageal squamous cell carcinoma (ESCC)

Abstract

Background: Tislelizumab, an anti-programmed cell death protein 1 antibody, has demonstrated a survival benefit as second-line treatment in ESCC. Here, we report interim analysis (IA) data from the phase 3 RATIONALE-306 study, which evaluated the efficacy and safety of tislelizumab plus chemotherapy vs placebo plus chemo- therapy in patients with advanced or metastatic ESCC in the first-line setting. Methods: In this randomized, double-blind, global study, adults with unresectable locally advanced or metastatic ESCC, with no prior systemic treatment for advanced disease were enrolled regardless of programmed death-ligand 1 (PD-L1) expression status. Patients were randomized (1:1) to receive tislelizumab 200 mg (Arm A) or placebo (Arm B) intravenously once every three weeks, both in combination with investigator-chosen chemotherapy (ICC; platinum [cisplatin or oxaliplatin] and fluo- ropyrimidine [capecitabine or 5-FU] or platinum and paclitaxel) until disease pro- gression per RECIST v1.1, intolerable toxicity, or withdrawal. Randomization was stratified by geographic region, prior definitive therapy and ICC. The primary endpoint was overall survival (OS) in the intent-to-treat (ITT) population. Hierarchical sequentially-tested secondary endpoints were progression-free survival (PFS), objec- tive response rate (ORR) by the investigator, OS in the PD-L1 score ≥10% subgroup, and health-related quality of life. Other secondary endpoints included duration of response (DoR) by the investigator, and safety. Results: Of 649 patients enrolled from 16 countries/4 regions (74.9% and 25.1% from Asia and non-Asian countries [Europe, Oceania, and North America]), 326 and 323 patients were randomized to Arms A and B, respectively (ITT population). At data cutoff (28/02/2022), median follow-up was 16.3 and 9.8 months in Arms A and B, respectively. The study met its primary endpoint at IA by demonstrating statistically significant improvement in OS in Arm A vs Arm B (median OS: 17.3 vs 10.6 months; HR 0.66 [95% CI 0.54, 0.80], p<0.0001). OS improvement was consistently observed across prespecified subgroups including ICC option, region, and PD-L1 expression status. In patients with PD-L1 score ≥10%, Arm A also demonstrated significant improvement in OS vs Arm B (median OS: 16.8 vs 10.0 months, HR 0.61 [95% CI 0.44, 0.85], p=0.0017). A significant improvement in PFS was observed in Arm A vs Arm B (median PFS: 7.3 vs 5.6 months; HR 0.62 [95% CI 0.52, 0.75], p<0.0001). Arm A was associated with a higher ORR (63.5% vs 42.4%, odds ratio 2.38 [95% CI 1.73, 3.27], p<0.0001) and more durable response (median DoR: 7.1 [95% CI 6.1, 8.1] vs 5.7 months [95% CI 4.4, 7.1]) than Arm B. Overall, similar proportions of patients in Arms A and B had ≥1 treatment-related treatment-emergent adverse event (TRAE; 96.6% and 96.3%), ≥Grade 3 TRAEs (66.7% vs 64.5%), and TRAEs leading to death (1.9% vs 1.2%), respectively. Serious TRAEs occurred in 28.7% vs 19.3%, and treatment- emergent AEs leading to discontinuation occurred in 31.8% vs 22.4% in Arms A vs B. No new safety signal for tislelizumab was observed. Conclusions: Tislelizumab plus chemotherapy as first-line treatment demonstrated a statistically significant and clinically meaningful improvement in OS over placebo plus chemotherapy in patients with advanced or metastatic ESCC, with a manageable safety profile.