Xinyu Mei

Supplementary Figure S1. Study design.

Supplementary Figure S3. Waterfall plots of best percent change from baseline in target lesion sum of diameters by investigator assessment in (A) PET responders and (B) PET nonresponders (safety analysis set).

Purpose:The aim of this study is to assess positron emission tomography/computed tomography (PET/CT)–guided neoadjuvant treatment with tislelizumab plus chemotherapy/chemoradiotherapy in patients with resectable esophageal squamous cell carcinoma (ESCC).Patients and Methods:RATIONALE-213, a multicenter, open-label, two-cohort phase II study, enrolled 70 patients with resectable ESCC. After one induction chemotherapy cycle, patients were categorized as PET responders (PET maximum standardized uptake value decrease ≥35%) or PET nonresponders (<35%). Subsequently, all patients received three cycles of tislelizumab 200 mg intravenously. In addition, PET responders received chemotherapy and PET nonresponders received chemoradiotherapy as neoadjuvant treatment followed by surgery. The primary endpoint was the pathologic complete response (pCR) rate.Results:As of October 25, 2024 (median follow-up 25.5 months), pCR rates were 30% [95% confidence interval (CI), 11.9–54.3] in PET responders and 34.4% (95% CI, 18.6–53.2) in PET nonresponders. Higher pCR rates were associated with higher baseline programmed cell death ligand 1 tumor area positivity scores in both cohorts. One-year disease-free survival rates were 79% and 74.2%, and event-free survival rates were 87.1% and 67.8%, respectively. Any-grade and grade ≥3 treatment-related adverse events (TRAE) occurred in 93.3% and 50% of PET responders and 97.5% and 82.5% of PET nonresponders, with no new safety signals. The most common grade ≥3 TRAE was decreased neutrophil count (36.7% and 70%, respectively).Conclusions:Tislelizumab with chemotherapy/chemoradiotherapy as neoadjuvant treatment for resectable ESCC yielded promising pCR rates and favorable survival outcomes with a tolerable safety profile in both PET/CT-guided responders and PET nonresponders.

Supplementary Figure S6. Change in expression of indicated signatures between baseline and post-treatment in PET nonresponders (A–D). Change in PD-L1 TAP scores between baseline and post-treatment in (E) PET responders and (F) PET nonresponders.

Supplementary Figure S4. Kaplan–Meier plot of OS (safety analysis set).

Supplementary Figure S5. Comparison of immune-related and tumor-intrinsic signatures at baseline between PET responders and PET nonresponders (A) and indicated signatures between patients with and without pathological response in (B, C) PET responders and (D, E) PET nonresponders.

Supplementary Table S1. RATIONALE-213 ethics approval. Supplementary Table S2. Representativeness of study participants. Supplementary Table S3. Summary of treatment exposure to tislelizumab. Supplementary Table S4. Summary of treatment exposure to chemotherapy. Supplementary Table S5. Summary of treatment exposure to radiotherapy. Supplementary Table S6. Baseline characteristics of surgical and nonsurgical patients by PET response status. Supplementary Table S7. Summary of surgery (safety analysis set). Supplementary Table S8. Subgroup analyses of pathological response by baseline clinical characteristics. Supplementary Table S9. Analysis of pathological response assessed by local pathologist by baseline PD-L1 status (efficacy-evaluable analysis set). Supplementary Table S10. Analysis of disease response by investigator per RECIST v1.1 (safety analysis set with measurable disease at baseline). Supplementary Table S11. Disease recurrence by PET response status. Supplementary Table S12. TRAEs with ≥10% incidence (safety analysis set). Supplementary Table S13. Summary of surgery-relevant adverse events (efficacy-evaluable analysis set). Supplementary Table S14. Summary of all deaths (safety analysis set). Supplementary Table S15. Baseline demographic and clinical characteristics (efficacy- and GEP-evaluable populations).

Supplementary Figure S2. Distribution of residual viable tumor percentages in non-pCR patients by PET response status