Comparison of Nanoliposomal Irinotecan Plus Fluorouracil/Leucovorin and S-1, Irinotecan, and Oxaliplatin as Second-Line Chemotherapy After Gemcitabine Plus Nab-Paclitaxel for Unresectable Pancreatic Cancer.

OBJECTIVES: The optimal second-line chemotherapy after gemcitabine plus nab-paclitaxel (GnP) for unresectable pancreatic cancer (PC) remains unclear. This study compared the efficacy and safety of nanoliposomal irinotecan plus fluorouracil/leucovorin (NFF) and S-1, irinotecan, and oxaliplatin (S-IROX) after GnP failure. METHODS: This single-center retrospective cohort study included patients with unresectable PC refractory to GnP who received NFF or S-IROX between July 2020 and June 2024. Progression-free survival (PFS), overall survival (OS), tumor response, and adverse events were evaluated. Prognostic factors were also assessed with subgroup analyses. RESULTS: Seventy-nine patients were analyzed (NFF, n = 55; S-IROX, n = 24). Median PFS was significantly longer with S-IROX than with NFF (6.29 vs. 3.45 months; p = 0.048), and the overall response rate was higher (29% vs. 9%; p = 0.038). Median OS did not differ significantly (12.81 vs. 10.64 months; p = 0.170). The incidence of grade ≥ 3 adverse events was comparable. Multivariate analysis identified S-IROX, modified Glasgow Prognostic Score (mGPS) 0, and CA19-9 < 373 IU/L as independent predictors of longer PFS, while mGPS 0 and CA19-9 < 373 IU/L were associated with longer OS. Subgroup analyses showed favorable outcomes with S-IROX in locally advanced disease. CONCLUSIONS: S-IROX may be an effective and safe second-line option after GnP, particularly for locally advanced PC.