NALIRIFOX versus liposomal irinotecan plus fluorouracil/leucovorin as the second-line chemotherapy in gemcitabine refractory pancreatic adenocarcinoma: a real-world study

Background: Pancreatic adenocarcinoma has a high mortality rate. Nanoliposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI/FL) is the standard second-line chemotherapy after gemcitabine-based therapy. Although nanoliposomal irinotecan plus oxaliplatin, fluorouracil, and leucovorin (NALIRIFOX) has shown superior efficacy as first-line therapy over gemcitabine and nab-paclitaxel, its roles as second-line therapy remains undefined. Objectives: We aimed to compare the clinical outcomes and safety profiles of NALIRIFOX and nal-IRI/FL when used as a second-line treatment for patients with pancreatic adenocarcinoma who have progressed on a gemcitabine-based therapy. Designs: This was a single-center retrospective cohort study. Methods: We included patients with locally advanced or metastatic pancreatic adenocarcinoma who received NALIRIFOX or nal-IRI/FL following progression on first-line gemcitabine-based therapy from September 2020 to October 2024. Results: A total of 62 patients in the NALIRIFOX group and 131 in the nal-IRI/FL group were analyzed. Cumulative dose intensity ⩾80% over four cycles was achieved in 81.4% of the NALIRIFOX group and 73.1% of the nal-IRI/FL group ( p = 0.32). The median progression-free survival (PFS) was 4.0 months (95% confidence interval (CI): 3.6–4.5) in the NALIRIFOX group versus 2.5 months (95% CI: 2.1–3.0) in the nal-IRI/FL group (hazard ratio (HR): 0.686; 95% CI: 0.497–0.947; p = 0.021), and the median overall survival was 7.0 months (95% CI: 5.0–9.1) versus 6.3 months (95% CI: 4.4–8.1), respectively ( p = 0.827). Of the patients with disease progression after nal-IRI/FL, 69.1% received oxaliplatin-containing chemotherapy. Grade 3–4 adverse events were more frequent with NALIRIFOX, including febrile neutropenia, neutropenia, thrombocytopenia, and peripheral neuropathy; however, most were transient and manageable. Conclusion: NALIRIFOX provides superior PFS compared to nal-IRI/FL as second-line therapy for advanced or metastatic pancreatic cancer after gemcitabine failure. Although NALIRIFOX was associated with higher rates of hematologic and neurologic toxicities, they were manageable with careful monitoring.