Background: CA19-9 correlates with response to therapy and OS in patients with mPAC. NAPOLI-1 evaluated nal-IRI, a nanoliposomal formulation of irinotecan, with or without 5-FU/LV vs 5-FU/LV in mPAC patients previously treated with gem-based therapy. nal-IRI+5-FU/LV significantly improved OS (primary endpoint) vs 5-FU/LV (6.1 mo vs 4.2 mo; unstratified hazard ratio [HR] = 0.67; P = 0.012). CA19-9 response (≥50% decline from baseline) was superior with nal-IRI+5FU/LV vs 5-FU/LV (29% vs 9%; P = 0.0006). nal-IRI alone did not show a statistical improvement in OS. Methods: Patients with baseline CA19-9 measurements were divided into quartiles to evaluate the treatment effect pattern of CA19-9 in the nal-IRI+5-FU/LV and 5-FU/LV arms. Quartile ranges were based on 404 available CA19-9 values from randomized patients (N = 417). Unstratified Cox proportional hazards regression was used to estimate HRs and 95% confidence intervals (CIs). Effect of baseline CA19-9 on OS, time to response, progression-free survival (PFS), and response were assessed. Results: Of patients randomized to receive nal-IRI+5-FU/LV (n = 117) or 5-FU/LV enrolled contemporaneously (n = 119), 218 received study drug and had a baseline CA19-9 measurement. nal-IRI+5-FU/LV had a greater treatment effect on OS and PFS with higher CA19-9 level relative to 5-FU/LV. Higher treatment termination rates occurred in both study arms with higher CA19-9 quartile, but no patterns of subsequent therapy were observed. Conclusions: In patients with mPAC previously treated with gem-based therapy, nal-IRI+5-FU/LV significantly improved OS, supported by PFS and response rate. CA19-9 serum levels can provide important information with regard to OS. Clinical trial information: NCT01494506