Sequential chemo-immunotherapy as a novel bridging strategy for non-complete responders after neoadjuvant chemoradiotherapy in esophageal cancer: First prospective phase 2 trial challenging the immediate-surgery paradigm.

4066 Background: Locally advanced esophageal squamous cell carcinoma (LA-ESCC) patients with non-clinical complete response (non-CCR) after neoadjuvant chemoradiotherapy (NCRT) face >50% recurrence risk with direct surgery (DS), yet no standardized bridging strategy exists. This first study evaluates the efficacy and safety of sequential chemo-immunotherapy (SCI) as a bridge to surgery in this population. Methods: In this phase 2 cohort study (NCT05189730), 169 LA-ESCC pts who underwent NCRT were prospectively enrolled from June 2021 to January 2025. The NCRT regimen included paclitaxel and carboplatin every 3 weeks for two cycles. Concurrent radiotherapy (40–41.4 Gy) was administered. Post-NCRT, patients were assessed for non-CCR and stratified into two groups: the SCI group received two additional cycles of chemotherapy and tislelizumab (200 mg intravenously every 3 weeks) before surgery, while the DS group proceeded to surgery. The primary endpoint was pCR rate, secondary endpoints included major pathological response (MPR) rates and safety. Results: Eighty-seven non-CCR pts were included (SCI: n = 54; DS: n = 33). The median age was 63 years, with 78.0% male patients. Most patients were stage IIIB(83.9%). Surgery rates were 85.2% in the SCI group (46/54) and 81.8% in the DS group (27/33). In the ITT population, SCI significantly improved pCR rates (40.7% [22/54] vs. 18.1% [6/33]; OR: 3.06, p = 0.024, , one-sided Fisher's Exact Test) and showed a trend toward higher MPR rates (51.8% [28/54] vs. 33.3% [11/33]; OR: 2.14, p = 0.071). In the PP population, pCR rates remained higher in SCI (47.8% [22/46] vs. 22.2% [6/27]; OR: 3.16, p = 0.026) and showed higher MPR rates (60.9% [28/46] vs. 40.7% [11/27]; OR: 2.02, p = 0.078) . At 12 months, PFS rates were 95.6% in the SCI group versus 77.3% in the DS group (p = 0.094) in the ITT population, and 97.4% versus 77.8% (p = 0.064) in the PP population. SCI-related adverse events included lymphopenia (97.7%), leukopenia (84.6%), and fatigue (50.0%). In the no-surgical pts in SCI group, three cases experienced immune pneumonitis and thyroid dysfunction, respectively. Treatment-related adverse events in the SCI group included lymphopenia (97.7%), leukopenia (84.6%), and fatigue (50.0%).The main postoperative complications in the SCI group and DS group were anastomotic leakage and recurrent laryngeal nerve injury (3/46 vs. 2/27, P = 0.629). No significant treatment-related adverse events occurred in the SCI group. Conclusions: This pioneering study demonstrates that SCI as a bridging strategy significantly improves pCR rates by >2-fold (OR>3) and shows promising PFS trends with manageable toxicity in non-CCR LA-ESCC, challenging the immediate surgery paradigm. These results warrant validation in randomized phase 3 trials to redefine standard-of-care. Clinical trial information: NCT05189730 .