First-Line Tislelizumab Plus Chemotherapy for Esophageal Squamous Cell Carcinoma with Programmed Death-Ligand 1 Expression ≥ 1%: A Retrospective Analysis of RATIONALE-306.

Introduction: The United States Food and Drug Administration Oncologic Drugs Advisory Committee voted (September 2024) against the use of programmed cell death protein-1 inhibitors for first-line treatment of advanced or metastatic unresectable esophageal squamous cell carcinoma (ESCC) with a programmed death-ligand 1 (PD-L1) expression Tumor Area Positivity (TAP) score < 1% or combined positive score < 1 due to an unfavorable benefit-risk profile observed across the phase 3 CheckMate 648, KEYNOTE-590, and RATIONALE-306 trials. Therefore, we conducted a retrospective analysis of RATIONALE-306 to evaluate the efficacy and safety of tislelizumab plus investigator-chosen chemotherapy (ICC) versus placebo plus ICC in patients with advanced or metastatic unresectable ESCC and a PD-L1 TAP score ≥ 1%.

Methods: Adult patients with advanced or metastatic unresectable ESCC enrolled in the global, randomized, phase 3 RATIONALE-306 trial randomly received tislelizumab 200 mg every 3 weeks plus ICC or matched placebo plus ICC. Efficacy and safety outcomes were evaluated among patients who were retrospectively assessed for PD-L1 expression defined by a TAP score ≥ 1%.

Results: At primary analysis data cutoff (February 28, 2022), a clinically meaningful improvement in median overall survival was observed among 230 patients in the tislelizumab plus ICC arm {16.8 [95% confidence interval (CI) 15.3-20.8] months} versus 248 patients in the placebo plus ICC arm [9.6 (95% CI 8.9-11.8) months] [stratified hazard ratio 0.64 (95% CI 0.51-0.80)]; this was maintained at a 3-year follow-up data cutoff (November 24, 2023). Similar findings at primary analysis were observed for progression-free survival, objective response rate, disease control rate, and duration of response. Tislelizumab plus ICC was tolerable and no new safety signals were observed.

Conclusions: Tislelizumab plus ICC is an effective and well tolerated first-line treatment option for patients with advanced or metastatic unresectable ESCC and a tumor PD-L1 TAP score ≥ 1%.

Trial Registration Number: ClinicalTrials.gov NCT03783442.