A post-hoc analysis of the RATIONALE-306 trial demonstrated that the addition of tislelizumab to chemotherapy in the first-line setting offers substantial and clinically meaningful efficacy improvements in patients with locally advanced oesophageal squamous cell carcinoma (ESCC), compared to placebo plus chemotherapy.
Previously published data from the global phase III RATIONALE-306 trial showed that tislelizumab combined with chemotherapy significantly and durably improved overall survival (OS) compared to placebo plus chemotherapy in the first-line treatment of patients with advanced or metastatic ESCC.1,2 Median OS was 17.2 months with tislelizumab plus chemotherapy compared to 10.6 months with placebo plus chemotherapy (HR[95% CI]: 0.70[0.59-0.83], p< 0.0001).1,2
Tislelizumab in combination with platinum-based chemotherapy received EMA approval for the first-line treatment of adult patients with HER2-negative locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumours express PD-L1 with a tumour area positivity (TAP) score of at least 5%.3
At ESMO GI 2025, a post-hoc subgroup analysis of the RATIONALE-306 trial was presented, focusing specifically on patients with locally advanced ESCC, including a further subset of patients whose tumours had a PD-L1 TAP score of at least 5%.4
The subgroup analysis retrospectively identified patients with non-metastatic ESCC from the RATIONALE-306 trial who were deemed unfit for surgery or definitive chemoradiation. These patients had previously been randomised in a 1:1 ratio to receive either tislelizumab plus chemotherapy or placebo plus chemotherapy as part of the original trial, which had enrolled patients with unresectable locally advanced or metastatic ESCC without prior systemic treatment for advanced disease.
In total, 88 of the 649 participants in the RATIONALE-306 trial (13.6%) were retrospectively selected and included. Among these, 45 patients (51.1%) had a tumour PD-L1 TAP score ≥5%. Baseline demographic and disease characteristics in this subgroup were consistent with those of the intention-to-treat (ITT) population of the trial.
Tislelizumab plus chemotherapy improved OS compared to placebo plus chemotherapy in all patients with locally advanced ESCC (median OS: 25.6 vs 12.3 months; HR[95% CI]: 0.49[0.29-0.84], p= 0.0037). Among patients whose tumours expressed PD-L1 with a TAP score ≥5%, median OS was 26.4 months with tislelizumab plus chemotherapy compared to 11.5 months with placebo plus chemotherapy (HR[95% CI]: 0.37[0.16-0.83], p= 0.0067). For all patients with locally advanced ESCC, median PFS was 9.7 months with tislelizumab plus chemotherapy compared to 6.9 months with placebo plus chemotherapy (HR[95% CI]: 0.56[0.31-1.01], p= 0.0262). Among those with a tumour PD-L1 TAP score ≥5%, median PFS was 13.2 months and 6.7 months, respectively (HR[95% CI]: 0.44[0.19-1.02], p= 0.0269).
In terms of tumour response, tislelizumab plus chemotherapy achieved a higher objective response rate (ORR) than placebo plus chemotherapy. Among all patients with locally advanced disease, ORR was 61.2% vs 38.5%, respectively. For those with PD-L1 TAP scores ≥5%, ORR was 68.0% with tislelizumab plus chemotherapy and 30.0% with placebo plus chemotherapy. Additionally, the median duration of response was longer in the tislelizumab group: 12.6 vs 7.1 months in the full subgroup, and 22.1 vs 5.7 months in the PD-L1-positive subgroup.
The safety profile of tislelizumab plus chemotherapy in patients with locally advanced ESCC was consistent with the overall population in the RATIONALE-306 trial. No new safety signals emerged. The most common grade ≥3 treatment-related adverse event in the locally advanced ESCC subgroup was decreased neutrophil count, occurring in 26.5% of patients receiving tislelizumab plus chemotherapy and 10.3% of those receiving placebo plus chemotherapy. These findings were consistent with the rates observed in the broader ITT population, where decreased neutrophil counts occurred in 30.9% and 32.7% of patients in the respective treatment arms.
This post-hoc analysis highlights the potential value of tislelizumab plus chemotherapy as first-line treatment strategy for patients with locally advanced ESCC who are not candidates for surgery or definitive chemoradiation. The observed improvements in OS, PFS, and response durability provide a strong rationale for considering first-line tislelizumab plus chemotherapy in this subset of patients, particularly those with PD-L1-positive tumours.
References
1. Xu J, Kato K, Raymond E, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol 2023;24(5):483-95.
2. Yoon HH, Kato K, Raymond E, et al. Global, randomized, phase III study of tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced/metastatic esophageal squamous cell carcinoma (RATIONALE-306 update): minimum 3-year survival follow-up. J Clin Oncol 2024;42(Suppl 16):4032.
3. European Medicines Agency. Tevimbra 100 mg concentrate for solution for infusion. Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/tevimbra-epar-product-information_en.pdf (last accessed 7 July 2025).
4. Van Cutsem E, Xu J, Raymond E, et al. Tislelizumab (TIS) + chemotherapy (CT) vs placebo (PBO) + CT in patients (pts) with locally advanced (LA) esophageal squamous cell carcinoma (ESCC): RATIONALE-306 subgroup analysis. Presented at ESMO GI 2025; Abstract 389MO.
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