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: Kojima Takashi , Ogata Takashi , Ishihara Ryu , Hara Hiroki , Sun Tianmo , Xu Sheng , Kato Ken 
Published: January 2025

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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.