4100 Background: Cadonilimab plus chemotherapy is a promising treatment option in the first-line setting of gastric cancer; however, its activity in the neoadjuvant setting remains unclear. The study evaluated the efficacy and safety of cadonilimab plus chemotherapy in neoadjuvant treatment for locally advanced gastric or gastroesophageal junction (G/GEJ) cancer. Methods: Eligible patients with locally advanced G/GEJ cancer (cT3-4a N+ M0) were enrolled and treated with 3 cycles of SOX chemotherapy (oxaliplatin 130mg/m 2 , IV, d1; S-1 40-60 mg, PO, bid, d1-d14; q21d) plus cadonilimab (10mg/Kg IV, d1, q21d), followed by radical gastrectomy with D2 lymphadenectomy. The primary endpoint was pathological complete response (pCR) rate, and the secondary endpoints included R0 resection rate, major pathological response (MPR) rate, 2-year disease-free survival (DFS) rate, 2-year overall survival (OS) rate and safety. Moreover, a single-cell spatial proteomic atlas was constructed to identify the mechanisms of immune resistance in patients with G/GEJ cancer who received neoadjuvant cadonilimab combined with SOX chemotherapy. Results: From September 2023 to July 2024, 45 patients were screened, and 37 patients were enrolled in this study. The median age was 58 years (range 27–72). 26 (70.3%) patients had cT4a disease, and 32 (86.5%) patients had a primary tumor in the stomach. All patients underwent preoperative evaluation. Two (5.4%) patients refused surgery, and 35 (94.6%) patients underwent gastrectomy with D2 lymphadenectomy. pCR (TRG1a) was observed in nine patients (ITT set: 24.3% (95% CI: 11.8% to 41.2%); surgery set: 25.7% (95% CI: 12.5% to 43.3%)). The MPR (TRG1a/b) rate was 70.3% (95% CI: 53.0% to 84.1%). As of the cutoff date of January 1, 2026, the median follow-up time was 24.1 months (range 14.3-28.4). One patient who refused surgery died, and three patients in the surgery set relapsed. 2-year DFS and OS rates were 90.2% and 97.3, respectively. Most of the TRAEs were grade 1-2. Nine (24.3%) patients experienced grade 3-4 TRAEs. The most common grade 3-4 TRAEs were thrombocytopenia (n = 4, 10.8%) and rash (n = 2, 5.4%). Single-cell spatial atlas demonstrates that recurrence following cadonilimab combined with SOX chemotherapy in gastric cancer is associated with distinct spatial immune ecosystems, which is characterized by immune deserts or suppressive fibrotic–myeloid networks that spatially and functionally incapacitate CD8 T cells. Conclusions: Based on the encouraging pCR rate, survival outcome and manageable safety in this study, cadonilimab plus SOX chemotherapy is a promising neoadjuvant treatment option for patients with locally advanced gastric cancer. Moreover, targeting stromal and myeloid components may be necessary to unlock the full therapeutic potential of immune checkpoint blockade. Clinical trial information: NCT05948449 .
Zhang et al. (Wed,) studied this question.