Phase II trial of neoadjuvant nivolumab and SOX in resectable gastric/gastroesophageal junction cancer: Therapeutic response and biomarker correlations.

2622 Background: Neoadjuvant immunotherapy produces a major pathologic response (MPR) in 40% of patients with locally advanced gastric cancer (LAGC). Herein, we conducted a phase prospective clinical study to investigate markers related to the response to neoadjuvant immunotherapy. Methods: Patients with locally advanced gastric or gastro-esophageal junction cancer (cT3-4N+M0,CY0,P0) were enrolled and received either 3 preoperative and 3 postoperative cycles of nivolumab (360 mg, IV, d1, Q21d) plus SOX regimen (oxaliplatin 130 mg/m 2 , IV, d1 with oral S-1 40-60mg, bid, d1-d14, Q21d ) therapy, followed by 11 cycles of nivolumab monotherapy. The primary endpoint was the pCR rate, while the mPR, 3-year-DFS and 3-year-OS as the second endpoint. This clinical trial was registered at Clinicaltrial.gov (NCT05739045). In addition, tissue samples from patients before and after preoperative therapy were performed scRNA-seq to explore the changes of tumor microenvironment during the therapy and biomarkers associated with therapy response. Results: Forty-six patients were enrolled from November 2022 to March 2023, with a median age of 66 years (range, 34-74), and 38 (82.60%) were male. There were 28 (60.87%) patients with PD-L1 CPS ≥5. The study achieved its primary endpoints, with a pCR rate of 21.74% and an MPR rate of 41.30%. Among the 46 patients who underwent D2 gastrectomy, the 1-year OS rate was 97.83% and 1-year DFS rate was 95.65%. Single-cell RNA sequencing of 131 tumor samples obtained from 46 patients with LAGC at multiple time points during neoadjuvant therapy showing that the expression of MHC-II was upregulated in malignant cells in the pre-sensitive group. In a retrospective cohort of 226 patients treated with neoadjuvant immunotherapy, MHC-II-positive patients exhibited significantly higher rates of pCR and mPR compared to MHC-II-negative patients. Furthermore, 30 MHC-II-positive GC patients were prospectively enrolled to receive neoadjuvant immunotherapy, showing pCR and mPR rates of 36.67% and 66.67%, respectively. Mechanistically, we observed that T cell-induced IFN-γ signaling predominated in the tumor microenvironment of the sensitive group before treatment. This signaling pathway induces MHC-II expression in tumor cells, thereby enhancing the T cell-mediated antitumor immune response during neoadjuvant immunotherapy. In addition, MHC-II expression in tumor cells can be detected via IHC and commercially available antibodies in standard pathology laboratories, making it a potential biomarker to guide the selection of appropriate GC patients for neoadjuvant immunotherapy. ClinicalTrials.gov registration: NCT05739045. Conclusions: Our study illuminates the role of MHC-II expression in tumor cells in modulating the response to immunotherapy in gastric cancer. Clinical trial information: NCT05739045 .