Perioperative therapy with tifcemailmab plus toripalimab and chemotherapy for resectable thoracic esophageal squamous cell carcinoma (BT-NICE trial): A prospective phase II study.

4087 Background: Tifcemailmab is a first-in-class humanized monoclonal antibody targeting B- and T-lymphocyte attenuator (BTLA), a novel inhibitory immune checkpoint. This phase II BT-NICE trial represents the first clinical study designed to evaluate the efficacy and safety of a perioperative treatment regimen that combines a BTLA inhibitor (tifcemailmab), a PD-1 inhibitor (toripalimab), and chemotherapy for resectable thoracic ESCC. Methods: Patients(pts) with histologically confirmed, resectable thoracic ESCC (clinical stage cT1b-3N1-3M0 or cT2-3N0M0) were enrolled. They received 2 cycles of neoadjuvant therapy with tifcemailmab, toripalimab, and standard chemotherapy (every 3 weeks). Following radical esophagectomy, pts with a pathological complete response (pCR) received up to 15 cycles of adjuvant dual immunotherapy (tifcemailmab + toripalimab). Pts without a pCR received 2 cycles of adjuvant chemotherapy plus dual immunotherapy, followed by dual immunotherapy for up to 13 cycles. The primary endpoint was pCR rate. Secondary endpoints included major pathological response (MPR) rate, objective response rate (ORR), R0 resection rate, adverse events (AEs), event-free survival (EFS), and overall survival (OS). Results: Between October 20, 2024, and September 30, 2025, a total of 25 patients were successfully enrolled and underwent surgery after completing neoadjuvant therapy. The median age was 63 years (range 53-75), and 19 (76.0%) were male. Most pts (23/25, 92.0%) had stage III disease. The R0 resection rate was 100% (25/25). The ORR (neoadjuvant) was 96.0% (24/25). The MPR rate was 56.0% (14/25), and the pCR rate was 40.0% (10/25). Pathologic downstaging was achieved in 84.0% of patients. Grade 3-4 treatment-related AEs occurred in 24.0% (6/25) of pts, and grade 3-4 immune-related AEs occurred in 20.0% (5/25); the most common were rash and hypothyroidism. Overall postoperative complications were 20% (5/25). One pt experienced postoperative complications (pulmonary infection and anastomotic leakage). No treatment-related surgical delays or 30-day mortality occurred. Conclusions: The BT-NICE regimen demonstrates promising efficacy and is feasible with a manageable safety profile in pts with locally advanced, resectable ESCC. This study provides the first clinical evidence supporting the incorporation of a BTLA inhibitor into a perioperative treatment paradigm for ESCC. Clinical trial information: NCT06588335 .