First-line (1L) tislelizumab (TIS) plus chemotherapy (CT) vs placebo (PBO) plus CT in advanced/metastatic esophageal squamous cell carcinoma (ESCC): RATIONALE-306 Japanese subgroup analysis with longer follow-up.
Authors: Takashi Kojima, Takashi Ogata, Ryu Ishihara, Hiroki Hara, Tianmo Sun, Sheng Xu, Ken Kato
Journal: Journal of Clinical Oncology (2025)

420 Background: In the global phase 3 RATIONALE-306 study (NCT03783442), TIS + CT showed a significant overall survival (OS) benefit vs PBO + CT as 1L therapy for advanced/metastatic ESCC. After a minimum 3-year follow-up, the hazard ratio (HR) for OS was 0.70 for all randomized patients (pts) and for pts with programmed death-ligand 1 (PD-L1) Tumor Area Positivity (TAP) score ≥10%.We report results for the Japanese subgroup. Methods: Eligible pts enrolled in Japan were randomized (1:1) to receive intravenous TIS 200 mg or PBO every 3 weeks + investigator-chosen CT (platinum + fluoropyrimidine/paclitaxel) until disease progression or intolerable toxicity. The primary endpoint was OS in the intent-to-treat (ITT) population. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and OS in pts with PD-L1 TAP score ≥10%. Results: Of 649 randomized pts, 66 (10.2%) were Japanese, median age was 67 years, 89.4% were male, and 28.8% had PD-L1 TAP score ≥10%. At study entry, Eastern Cooperative Oncology Group performance status was 0 for 77.3% pts and 97.0% had metastatic disease. As of Nov 24, 2023, 78.8% vs 84.8% Japanese pts on TIS + CT vs PBO + CT received post-systemic therapy (ITT: 51.5% vs 57.9%). After a minimum follow-up of 37.9 months, TIS + CT showed improvements vs PBO + CT in median OS (24.5 vs 15.1 months [mo]; HR: 0.75) in all pts and in pts with PD-L1 TAP score ≥10% (HR: 0.79), median PFS (HR: 0.77) and ORR (63.6% vs 45.5%) (Table). Treatment-related adverse events (TRAEs) with TIS + CT vs PBO + CT in Japanese pts were 45.5% vs 36.4% for any grade (ITT: 69.8% vs 60.7%); 27.3% vs 6.1% for grade ≥3 (ITT: 32.1% vs 20.2%); 24.2% vs 3.0% for serious TRAEs (ITT: 19.8% vs 8.4%); TRAEs led to treatment discontinuation in 3.0% vs 6.1% (ITT: 13.3% vs 6.5%). No TRAEs leading to death were reported in Japanese pts (ITT: 1.5% vs 0.6%). Conclusions: After 3 years, TIS + CT continued to demonstrate robust efficacy and a tolerable safety profile in Japanese pts as 1L therapy for advanced/metastatic ESCC in the RATIONALE-306 study, consistent with the overall population. Clinical trial information: NCT03783442 . Efficacy outcomes. JapanTIS + CT(n=33) JapanPBO + CT(n=33) OverallTIS + CT(n=326) OverallPBO + CT(n=323) Median OS, mo (95% CI) 24.5 (17.6, 26.9) 15.1 (8.0, 22.5) 17.2 (15.8, 20.1) 10.6 (9.3, 12.1) HR (95% CI) 0.75 (0.43, 1.30) - 0.70 (0.59, 0.83) b - PD-L1 TAP score ≥10%, n (%) 12 (36.4) 7 (21.2) 116 (35.6) 107 (33.1) Median OS by PD-L1 TAP score ≥10%, mo (95% CI) 25.5(10.9, NE) 16.8(0.9, NE) 16.6(15.3, 23.4) 10.0(8.6, 13.3) HR (95% CI) 0.79 (0.26, 2.36) - 0.70 (0.52, 0.95) b - Median PFS a , mo (95% CI) 6.8 (4.4, 8.5) 4.5 (4.1, 6.7) 7.3 (6.9, 8.3) 5.6 (4.9, 6.0) HR (95% CI) 0.77 (0.45, 1.32) - 0.60 (0.50, 0.72) b - ORR a , n (%) 21 (63.6) 15 (45.5) 207 (63.5) 137 (42.4) a Investigator assessed. b Stratified. CI, confidence interval; NE, not estimable.