Efficacy and safety of neoadjuvant toripalimab plus chemotherapy in localized deficient mismatch repair/microsatellite instability-high gastric or esophagogastric junction adenocarcinoma (NICE): a multicentre, single-arm, exploratory phase 2 study.

Background: In locally advanced gastric or gastroesophageal junction adenocarcinoma (GC/EGJC), deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumors exhibit high responsiveness to immunotherapy. The synergistic efficacy of neoadjuvant immunotherapy combined with chemotherapy in dMMR/MSI-H GC/EGJC remains uncertain.

Methods: The NICE trial is a multicentre, single-arm, exploratory phase 2 study conducted at six hospitals in China, evaluating the safety and efficacy of toripalimab in combination with CapeOX as perioperative therapy for locally advanced GC/EGJC across three biomarker-defined cohorts. This report presents findings from cohort C. Eligible patients were aged 18-75 years with histologically or cytologically confirmed GC/EGJC, confirmed dMMR/MSI-H status, and clinically staged as cT3-4aNxM0 or cT2N + M0 (AJCC 8th edition) based on contrast-enhanced CT or MRI, upper endoscopy, diagnostic laparoscopy, and peritoneal lavage cytology. Patients received four cycles of neoadjuvant toripalimab (240 mg IV every 3 weeks) plus CapeOX (capecitabine 1000 mg/m² orally twice daily on Days 1-14 and oxaliplatin 130 mg/m² IV on Day 1), followed by curative-intent surgery and up to four cycles of the same regimen as adjuvant therapy. The primary endpoint was the major pathological response (MPR) rate, defined as ≤10% residual viable tumor cells in the tumor specimen resected after neoadjuvant therapy. All patients who received at least one dose of treatment were included in the efficacy and safety analyses. The trial is registered with ClinicalTrials.gov, NCT04744649.

Findings: Between March 12, 2021 and June 1, 2024, twenty-two patients were screened, with sixteen meeting the inclusion criteria and undergoing treatment. Tumor stages were cT2N1 (n = 1), cT3N0-3 (n = 3), and cT4aN1-3 (n = 12). Fifteen patients completed four cycles of therapy preoperatively, while one patient completed two cycles due to adverse events. None of patients experienced disease progression. One patient achieved a complete clinical response as indicated by radiology and endoscopy and consequently refused surgery, while the remaining fifteen patients underwent resection. The R0 resection rate was 100% (15/15). The MPR rate was 93.3% (14/15), and the pathological complete response (pCR) rate was 80% (12/15). Six patients (37.5%, 6/16) experienced grade 3/4 treatment-related adverse events. One patient died of COVID-19 287 days post-surgery without relapse. No disease relapse was observed in any patient.

Interpretation: Given the small sample size and limited population diversity, these findings should be interpreted with caution. Nonetheless, neoadjuvant toripalimab combined with the CapeOX regimen is feasible for localized advanced dMMR/MSI-H GC/EGJC, demonstrating high MPR and pCR rates without unexpected adverse events.

Funding: Noncommunicable Chronic Diseases-National Science and Technology Major Project, Beijing Hospitals Authority Clinical Medicine Development, Beijing Natural Science Foundation, Key Clinical Technique of Guangzhou, Key Areas Research and Development Programs of Guangdong Province, National Natural Science Foundation of China, Natural Science Foundation of Guangdong Province, Clinical Research Program of Nanfang Hospital.