Perioperative tislelizumab plus chemotherapy versus chemotherapy in MHC-II positive/MHC-II negative locally advanced GC/GEJC: A prospective, randomized, open-label, biomarker-driven, phase 2 trial.

2513 Background: Neoadjuvant immunotherapy achieves major pathologic response (mPR) in 40% of locally advanced gastric cancer (LAGC) patients. Tumor-specific MHC-II expression(tsMHC-II) has been linked to a better enhanced response to immune checkpoint inhibitor therapy. Herein, we conducted a prospective, randomized study to evaluate the effectiveness of chemotherapy combined with anti-PD-1 therapy versus chemotherapy alone as neoadjuvant treatment for tsMHC-II-positive LAGC patients. Methods: Patients with locally advanced GC/GEJC (cT3-4N+M0, CY0, P0) were enrolled according to tsMHC-II expression. Within each stratum, patients were subsequently randomized 1:1 to receive either tislelizumab combined with chemotherapy or chemotherapy alone, including Arm A (tsMHC-II-positive, chemotherapy + tislelizumab), Arm B (tsMHC-II-positive, chemotherapy), Arm C (tsMHC-II-negative, chemotherapy + tislelizumab), Arm D (tsMHC-II- negative, chemotherapy). For experimental group, patients received either 3 preoperative and 3 postoperative cycles of tislelizumab plus SOX/XELOX, followed by 11 cycles of tislelizumab. For control group, patients received either 3 preoperative and 3 postoperative cycles of SOX/XELOX. The primary endpoint was mPR rate (Arm A vs. Arm B). The key secondary endpoint was pCR rate (Arm A vs. Arm B). This clinical trial was registered at Clinicaltrial.gov (NCT06374901). Results: 136 patients (34 per arm) were enrolled from July 2024 to March 2025, with a median age of 65 years (range, 30-75), and 105 (76.64%) were male. The study achieved its primary endpoint. The results revealed that tsMHC-II-positive patients in the tislelizumab plus chemotherapy group achieved a greater proportion of mPR (61.8% versus 26.5%; P = 0.003) and pCR (32.4% versus 8.8%; P = 0.016) than did those in the chemotherapy group, which met a prespecified endpoint. In contrast, this benefit was absent in tsMHC-II-negative patients (mPR: 23.5% vs 26.5%, P = 0.886; pCR: 5.9% vs 8.8%, P = 0.642). There were no significant differences in treatment-related adverse reactions among each group. Conclusions: In conclusion, compared with perioperative chemotherapy alone, the addition of tislelizumab to a given chemotherapy regimen significantly increased the proportion of mPR and pCR in tsMHC-II-positive patients with GAC/GEJAC only, which revealed that tsMHC-II could be a biomarker to guide the selection of appropriate GAC/GEJAC patients for perioperative immunotherapy. Clinical trial information: NCT06374901 .