Neoadjuvant PD-1 inhibitor combined with FLOT versus SOX for locally advanced gastric cancer: a retrospective cohort study

Zhenshun Li^1,2Xin Zhang^3,4Lili Duan^1,2Wanli Yang^1,2Liu Hong^1,2*

• ¹Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
• ²State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Xi'an, China
• ³Department of Radiology, Second Affiliated Hospital of Naval Medical University, Shanghai, China
• ⁴Department of Radiology, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, China

Background: Neoadjuvant immunochemotherapy is increasingly used for resectable locally advanced gastric cancer (LAGC) and gastroesophageal junction (EGJ) adenocarcinoma, yet the optimal chemotherapy backbone for PD-1 blockade remains unclear. We compared neoadjuvant PD-1 inhibitor plus S-1+oxaliplatin (SOX) versus PD-1 inhibitor plus 5-FU+oxaliplatin+Docetaxel+Leucovorin (FLOT) in a real-world cohort. Methods: This single-center retrospective study included patients with resectable, HER2-negative LAGC/EGJ adenocarcinoma (cT3–4b, any N+, M0; ECOG 0–1) treated between July 2020 and July 2025. Patients received neoadjuvant PD-1 inhibitor plus SOX or PD-1 inhibitor plus FLOT (3–5 cycles) followed by D2 gastrectomy. The primary endpoint was pathological complete response (pCR). Secondary endpoints included major pathological response (MPR), radiologic response (RECIST v1.1), perioperative outcomes, treatment-related adverse events (CTCAE v5.0), recurrence-free survival (RFS), and overall survival (OS). Survival was analyzed using Kaplan– Meier methods and Cox proportional hazards models. Results: Overall, 247 patients were enrolled (PD-1+SOX, n=141; PD-1+FLOT, n=106) with comparable baseline characteristics. Radiologic outcomes were similar between groups (ORR: 70.92% vs 66.98%, p=0.507; DCR: 87.23% vs 85.85%, p=0.752). Pathological responses did not differ significantly (pCR: 20.57% vs 16.98%, p=0.477; MPR: 37.59% vs 31.13%, p=0.292). Any-grade treatment-related adverse events occurred in 67.38% and 75.47% of patients, and grade ≥3 events in 19.15% and 26.42%, respectively; no treatment-related deaths occurred. R0 resection rates were high (100% vs 99.06%). Operative time and estimated blood loss were higher in the PD-1+FLOT group (p=0.010 and p=0.040), while postoperative complication rates were comparable. With median follow-up of 21 months (12–52) and 20 months (10–46), there were no significant differences in OS (HR 1.155, 95% CI 0.624–2.138) or RFS (HR 0.805, 95% CI 0.461–1.405). In multivariable analyses, non-MPR was an independent risk factor for both OS and RFS. Conclusions: Neoadjuvant PD-1 inhibitor plus SOX and plus FLOT yielded comparable response rates, survival outcomes, and safety profiles in patients with resectable LAGC/EGJ adenocarcinoma. PD-1+SOX was associated with less operative burden, and MPR remained independently associated with OS and RFS, supporting its value for risk stratification and treatment optimization.