Sorbitol-supplemented diet combined with neoadjuvant chemoimmunotherapy in locally advanced gastric cancer: Preliminary results from a randomized controlled trial.

Abstract

361 Background: Neoadjuvant chemoimmunotherapy is revolutionizing the treatment landscape for solid tumors. However, a subset of patients exhibited limited therapeutic response. Metabolomic profiling of non-responding patients revealed aberrant polyol pathway activation, with sorbitol accumulation identified as a novel immune-modulatory mechanism. To address this challenge , we initiated a randomized controlled trial evaluating the safety and efficacy of chemoimmunotherapy combined with a sorbitol-restricted diet in locally advanced gastric cancer (LAGC) patients. Methods: Key inclusion criteria were: age ≥ 18 years; histologically confirmed gastric cancer with locally advanced disease as defined by the AJCC 8th Edition; and no prior systemic anticancer therapy. Eligible patients were randomized 1:1 to receive either neoadjuvant chemoimmunotherapy (3-week cycles of SOX plus PD-1 antibody tislelizumab) combined with sorbitol-supplemented diet (2 g per dose, three times daily during treatment weeks； intervention group), or neoadjuvant chemoimmunotherapy (control group). The primary endpoint was the major pathological response (MPR) rate. Secondary endpoints included pathological complete response (pCR) rate, disease control rate (DCR), and R0 resection rate. Exploratory endpoints included treatment-related adverse events (TRAEs), progression-free survival (PFS), and overall survival (OS). Clinical trial registration: NCT06826079. Results: This interim analysis included the first 26 patients (13 per arm) of a planned 86-patient cohort. Demographic characteristics were comparable between groups, with the investigational arm comprising 8 males and 5 females (mean age 59 years, range 45-72) and the control arm 9 males and 4 females (mean age 56 years, range 48-68). Gastric signet ring cell carcinoma (GSRCC), prevalence showed a numerical trend favoring the investigational arm (46.2% vs 30.8%, p=0.42). Both groups demonstrated identical pCR rates (23.1%, 3/13 per arm), but the investigational arm exhibited superior MPR rates (61.5% vs 38.5%, p=0.039) and significantly higher ypN0 status achievement (76.9% vs 38.5%, p=0.012), with the GSRCC subgroup showing similar trends (MPR: 50% vs 25%; ypN0: 67.7% vs 25%). Both groups maintained 100% R0 resection and DCR rate. Safety profiles were comparable, with any-grade TRAEs occurring in 53.8% (7/13) of the investigational arm and 46.2% (6/13) of controls, and grade ≥3 TRAEs in 15.4% (2/13) per arm. Diarrhea was predominant in the investigational group, while leukopenia was most frequent in controls. Conclusions: This interim analysis demonstrates that the addition of a sorbitol-supplemented diet to neoadjuvant chemoimmunotherapy significantly enhances therapeutic efficacy in LAGC patients while maintaining a comparable safety profile. Clinical trial information: NCT06826079 .