Immunotherapy-based total neoadjuvant therapy versus neoadjuvant chemoradiotherapy in locally advanced esophageal squamous cancer: Interim results of a randomized phase 2 study.

Abstract

e16110 Background: Long-term outcomes of neoadjuvant chemoradiotherapy (nCRT) for locally advanced esophageal squamous cancer (LA-ESCC) are unsatisfactory. The short-term efficacy of concurrent nCRT and immunotherapy isn’t superior to that of nCRT. The use of total neoadjuvant therapy (TNT), which includes sequential chemotherapy and chemoradiation, is increasing in other malignancies and promises enhanced systemic disease control. The purpose of this study is to assess the efficacy and safety of the integration of tislelizumab, a PD-1 inhibitor with TNT (iTNT) in LA-ESCC. Here, we report our interim results. Methods: This is a prospective, single center, randomized, phase 2 trial. Eligible patients with thoracic LA-ESCC (cT1b-3N1-3M0 or cT3N0M0) were randomized in a 1:1:1 ratio into each of the three treatment arms and then surgery. All patients received nCRT (40Gy/20f with concurrent nab-paclitaxel and cisplatin). Arm A: nCRT followed by consolidation immunochemotherapy (ICT); Arm B: induction ICT followed by nCRT; Arm C: nCRT alone. The ICT regimen consisted of two 3-week cycles of tislelizumab plus nab-paclitaxel and cisplatin. The primary endpoint is the pathological complete response (pCR) rate, the secondary endpoints are R0 resection rate, 1-year and 2-year disease-free survival and overall survival and safety. Results: From February 2025 to December 2025, 90 patients were enrolled. At the time of writing, 65 patients (Arm A n = 19, Arm B n = 21, Arm C n = 25) completed neoadjuvant therapy and accepted surgery in per protocol set (PPS). One patient was inoperatable because of disease progression (Arm A), 9 patients are awaiting surgery; 15 patients remain on neoadjuvant treatment. Among the 65 patients who have received surgery, the incidence of grade ≥3 treatment-related adverse events during neoadjuvant treatment was 36.8% (7/19) for Arm A, 42.9% (9/21) for Arm B and 20.0% (5/25) for Arm C. No grade 5 TRAEs were reported. In Arm A, Arm B and Arm C groups, the rates of surgical complications of any grade were 63.2% (12/19), 47.6% (10/21) and 44.0% (11/25), respectively. Among these, the proportions of Clavien-Dindo grade 3-4 complications were 21.1% (4/19), 14.3% (3/21) and 8.0% (2/25), respectively. There was no postoperative 30-day mortality. All 65 patients achieved R0 resection. The pCR rate was 63.2% (12/19) in arm A, 76.2% (16/21) in arm B and 24.0% (6/25) in arm C (Table 1). The pCR rate was 70.0% (28/40) in the iTNT group (arm A + arm B). Conclusions: Immunotherapy-based TNT has achieved an encouraging pCR rate and a tolerable safety profile. Clinical trial information: ChiCTR2500098409. Pathological outcomes. Arm A (n=19) Arm B (n=21) Arm C (n=25) pCR 63.2% 76.2% 24.0% ypT0 63.2% 76.2% 40.0% ypN0/N1/N2-3 84.2% / 10.5% / 5.3% 90.5% / 0.0% / 9.5% 56.0% / 24.0% / 20.0%