Second-line 5-FU plus nanoliposomal irinotecan versus FOLFOX/XELOX in metastatic pancreatic cancer after gemcitabine–nab-paclitaxel failure: a propensity score-matched analysis

Background: There is limited evidence comparing second-line therapies following gemcitabine plus nab-paclitaxel (GemNab) in metastatic pancreatic ductal adenocarcinoma (PDAC). This study aimed to compare the effectiveness and safety of 5-fluorouracil plus nanoliposomal irinotecan (5-FU + Nal-IRI) versus oxaliplatin-based regimens (FOLFOX/XELOX) in this setting. Patients and methods: We retrospectively analyzed 445 patients with metastatic PDAC progressing after first-line GemNab, treated across 12 centers in Italy and Asia (2014-2024). Patients received either 5-FU + Nal-IRI (n = 180) or FOLFOX/XELOX (n = 265) as second-line therapy. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), overall response rate (ORR), and safety. Exact propensity score matching was carried out to reduce baseline imbalances. Results: In the matched cohort, median OS was 7.2 months [95% confidence interval (CI) 5.8-8.4 months] for 5-FU + Nal-IRI and 5.8 months (95% CI 4.1-6.8 months) for FOLFOX/XELOX [hazard ratio (HR) 0.74, 95% CI 0.58-0.95, P = 0.015], and median PFS was 3.0 months (95% CI 2.5-3.6 months) versus 2.5 months (95% CI 2.2-2.9 months), respectively (HR 0.75, 95% CI 0.61-0.91, P = 0.0048). ORR was similar (9% versus 10%, P = 0.79). Grade 3-4 adverse events were more frequent with 5-FU + Nal-IRI (31.1% versus 9.4%), particularly anemia (13.9% versus 1.7%) and diarrhea (5.6% versus 1.2%). FOLFOX/XELOX was associated with higher rates of any-grade thrombocytopenia and peripheral neuropathy. Conclusions: 5-FU + Nal-IRI showed a modest yet statistically significant survival advantage compared with FOLFOX/XELOX in patients with metastatic PDAC previously treated with GemNab, despite being associated with a higher incidence of adverse events. None the less, the selection of second-line therapy should be guided by a balanced evaluation of both efficacy and toxicity profiles.