Pathological complete response and ctDNA analyses in SCIENCE: Results from a randomized, phase III trial of neoadjuvant chemotherapy plus sintilimab and chemoradiotherapy plus sintilimab versus chemoradiotherapy in resectable locally advanced esophageal squamous cell carcinoma.

LBA4082 Background: The optimal neoadjuvant strategy for resectable locally advanced esophageal squamous cell carcinoma (RLA-ESCC) remains unclear. SCIENCE is a randomized phase III trial comparing neoadjuvant chemotherapy (nCT) plus sintilimab (S), neoadjuvant chemoradiotherapy (nCRT) plus S, and nCRT in RLA-ESCC, aiming to determine whether immunotherapy-based neoadjuvant therapy can improve efficacy without increasing toxicity or compromising surgical feasibility, and to explore ctDNA as an early molecular marker of treatment response. Methods: Pts with histologically confirmed, resectable thoracic ESCC (cT1N2–3M0 or cT2–4aN0–3M0 per AJCC/UICC 8th) were randomized 1:1:1 to nCT + S (A), nCRT + S (B), or nCRT (C), followed by surgery 6–8 weeks after neoadjuvant therapy. Co-primary endpoints were pCR and EFS. Longitudinal ctDNA was assessed (tumor-informed, personalized assay) at baseline, on-treatment, and preoperatively. pCR and EFS were compared using chi-square and log-rank tests, respectively, with overall two-sided α=0.05 controlled by allocating 0.02 to pCR and 0.03 to EFS. Interim analysis for pCR was prespecified. Results: At the time of data cutoff (Jan 19, 2026), 307 pts had completed neoadjuvant therapy and undergone surgery and were evaluable for pCR (Group A/B/C: 100/103/104). Most pts were male (88.3%) and had clinical stage III disease (81.4%). R0 resection was achieved in 303 pts (99 (99.0%) Group A; 102 (99.0%) Group B; 102 (98.1%) Group C). pCR rates were 18.0% in Group A, 57.3% in Group B, and 49.0% in Group C. Compared with Group A, pCR was significantly higher in Group B (OR 6.1, 95% CI 3.3–11.9; p<0.0001) and Group C (OR 4.4, 95% CI 2.3–8.5; p<0.0001). The safety profile was tolerable across three arms. Among 92 ctDNA-evaluable pts, detectability decreased from 96.7% at baseline to 48.9% preoperatively. Preoperative ctDNA positivity was significantly higher in Group A (78.6%) than in Group B (40.0%) and Group C (32.4%) (p<0.001). Importantly, on-treatment ctDNA status after cycle 1 was already associated with pathological response (p=0.0043). Pts with ctDNA clearance had higher pCR rates than those with persistent ctDNA (62.2% vs 9.1%, p<0.001). ctDNA clearance rates increased stepwise across pathological response categories: pCR (84.8%), MPR (48.1%), and non-responders (12.5%). Conclusion: Neoadjuvant CRT + S significantly improved pCR versus CT + S in RLA-ESCC. Preoperative ctDNA clearance status closely tracked pathological response, supporting ctDNA as a promising early molecular marker of treatment effect. EFS will be reported with longer follow-up. Clinical trial information: NCT05244798 . nCT + S nCRT + S nCRT pCR (95% CI) 18% (11, 26.9) 57.3% (47.2, 67) 49% (39.1, 59) P - value (vs. Group A) <0.0001 <0.0001 P - value (vs. Group B) 0.2942