Preoperative NALIRIFOX versus upfront surgery in high-risk resectable pancreatic cancer: A randomized, multi-center trial.

Abstract

711 Background: Neoadjuvant therapy is recommended for pancreatic cancer (PC) patients with high-risk features, although no standardized regimen currently exists. The NALIRIFOX regimen (liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin) has shown improved overall survival (OS) compared to gemcitabine plus nab-paclitaxel regimen in metastatic PC. This trial evaluates the efficacy and safety of perioperative NALIRIFOX compared to upfront surgery in patients with high-risk resectable PC. Methods: This randomized controlled, multicenter, open-label trial enrolled patients with high-risk resectable PC, defined by the following criteria: (1) radiologic evidence of resectable PC according to the 2024 NCCN guidelines; (2) CA19-9 levels ≥500 U/mL or a primary tumor diameter >3.0 cm. Patients were randomly assigned to perioperative chemotherapy with NALIRIFOX (Group A) or upfront surgery (Group B). The primary endpoint was 2-year OS rate. Secondary endpoints included resection rate, R0 resection rate, event-free survival (EFS), and safety. Results: As of September 2025, 26 patients were enrolled (Group A: n=14; Group B: n=12). The median age was 60 years (range: 48-69) in Group A and 61 years (42-70) in Group B, with median tumor diameters were 3.3 cm (range: 2.9-7.0) and 3.2 cm (range: 2.2-5.6), respectively. Baseline characteristics were generally balanced. In Group A, 9 patients underwent surgery, with R0 resection achieved in 7 (77.8%) patients. Five patients did not proceed to surgery: 2 continued neoadjuvant therapy, 2 discontinued due to progression, and 1 withdrew consent. In Group B, all 12 patients underwent surgery, with R0 resection in 11 (91.7%) patients. During neoadjuvant therapy, Group A exhibited a disease control rate of 91.7%. Among 7 evaluable patients, 6 (85.7%) achieved >50% reduction in CA19-9 from baseline, including 4 (57.1%) with >70% reduction. Grade ≥3 adverse events included neutropenia (42.9% vs. 33.3% in Groups A and B, respectively), elevated C-reactive protein (14.3% vs. 41.7%), and elevated procalcitonin (14.3% vs. 33.3%). Conclusions: The NALIRIFOX regimen shows a manageable safety profile in the perioperative treatment of high-risk resectable PC. Further follow-up is required to determine the survival benefits between the different treatment strategies. Clinical trial information: NCT06210360 .