Prognostic value of baseline biliary stents on outcomes in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) in the NAPOLI-1 trial (2018)

Introduction: In the NAPOLI-1 phase 3 study of patients with mPDAC who progressed following gemcitabine-based therapy (NCT01494506), nal-IRI+5-FU/LV significantly increased median overall survival (mOS) vs 5-FU/LV control (6.1 vs 4.2 months; unstratified hazard ratio [HR]=0.67 [0.49–0.92]; P = 0.012). Biliary stenting is used to treat malignant obstructive jaundice and associated complications, allowing bile efflux resulting in normalised bilirubin levels. Patients with a biliary stent were allowed to enter the NAPOLI-1 study if plasma bilirubin was normal. Methods: This post-hoc analysis explored outcomes in patients in the NAPOLI-1 study population with or without biliary stent at baseline (BL). Results: Prior to study entry, 37/417 (9%) patients had a biliary stent. A higher proportion of patients with a BL stent had a primary tumour located in the head of the pancreas at diagnosis vs patients without a BL stent (89% vs 58%). In the overall intent-to-treat (ITT) population, mOS and median progression-free survival (mPFS) were similar for patients with or without a BL stent (mOS: 5.3 vs 4.8 months, HR = 0.97, P = 0.90; mPFS: 3.5 vs 2.4 months, HR = 0.82, P = 0.32). Patients with a BL stent demonstrated a higher objective response rate (ORR) (16% vs 6%; P = 0.03) and a greater proportion of cancer antigen 19-9 (CA19-9) responses (37% vs 20%; P < 0.05) than those without. mOS was similar among patients in the nal IRI+5 FU/LV arm with (n = 15) vs without (n = 102) a BL stent (6.2 vs 6.1 months, HR = 0.91, P = 0.78); mPFS (4.5 vs 3.0 months, HR = 0.79, P = 0.47), ORR (27% vs 15%, P = 0.26) and CA19 9 responses (42% vs 27%, P = 0.31) were numerically lower. Patients with a BL stent receiving nal-IRI+5-FU/LV (n = 15) exhibited trends towards increased mOS (6.2 vs 5.2 months, HR = 0.44, P = 0.16) and ORR (27% vs 0, P = 0.26), improved mPFS (4.5 vs 1.5 months, HR = 0.21, P < 0.01), and similar CA19-9 responses (42% vs 40%, P = 1.00) vs patients receiving 5-FU/LV (n = 8). Patients without a BL stent receiving nal IRI+5 FU/LV (n = 102) had improved mOS (6.1 vs 4.2 months, HR = 0.68, P = 0.02), mPFS (3.0 vs 1.5 months, HR = 0.59, P < 0.01), ORR (15% vs 1%, P < 0.01) and CA19 9 responses (27% vs 8%, P < 0.01) vs patients receiving 5 FU/LV (n = 111). Treatment-related grade 3–4 adverse events were similar for patients with or without a BL stent, including infectious complications such as febrile neutropenia (overall safety population n = 1/34 vs n = 7/364; nal IRI+5 FU/LV arm n = 1/14 vs n = 1/103), diarrhoea (overall safety population n = 4/34 vs n = 48/364; nal-IRI+5-FU/LV arm n = 2/14 vs n = 13/103) and decreased neutrophil count (overall safety population n = 7/34 vs n = 43/364; nal IRI+5 FU/LV n = 2/14 vs n = 21/103). Incidence of dose modifications with nal IRI+5 FU/LV was broadly similar to the overall NAPOLI 1 population for patients with or without a BL stent. Conclusion: No clear prognostic effect of biliary stent at BL on efficacy outcomes was observed in patients with mPDAC who progressed on gemcitabine-based therapy, both in the NAPOLI-1 ITT population and the nal-IRI+5-FU/LV treatment arm. Both patients with and without a BL stent benefitted from treatment with nal-IRI+5-FU/LV compared with 5-FU/LV alone. These findings indicate that irrespective of the presence of a biliary stent before treatment initiation, nal-IRI+5-FU/LV is well-tolerated and can benefit patients with mPDAC who progressed on gemcitabine-based treatment.