NAPOLI-1 and NAPOLI-3 Trials

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The development of nanoliposomal irinotecan (nal-IRI) addressed the challenge of drug delivery in pancreatic adenocarcinoma’s dense stromal microenvironment. This formulation achieves 95% encapsulation with enhanced stability, longer half-life, and improved ability to penetrate leaky tumor vasculature. The nanoliposomal encapsulation enhances drug stability, penetration, retention, and intratumoral accumulation, potentially overcoming the hostile pancreatic cancer microenvironment that limits conventional drug delivery.

The NAPOLI-1 trial (NCT01494506), published in Lancet in 2016, represented the first global randomized phase 3 trial demonstrating survival benefit in second-line pancreatic cancer treatment. Patients with advanced disease who progressed on gemcitabine-based regimens were randomly assigned to receive infusional 5-FU/leucovorin alone vs the NALLIRI regimen (nal-IRI plus 5-FU/leucovorin). The trial met its primary end point with improved overall survival (HR 0.67, 33% relative risk reduction) and progression-free survival (HR 0.56), establishing level 1 evidence for second-line treatment sequencing.

Building on NAPOLI-1 success, the NAPOLI-3 trial (NCT04083235) brought nal-IRI to the frontline setting. Following extensive phase 1/2 optimization studies, the NALIRIFOX regimen was developed using nal-IRI 50 mg/m², oxaliplatin 60 mg/m², leucovorin 400 mg/m², and infusional 5-FU 2400 mg/m² over 46 hours. This global phase 3 trial of 770 patients across 180 centers in 18 countries demonstrated superiority over gemcitabine plus nab-paclitaxel, with a median survival of 11.1 vs 9.2 months (HR 0.83, 17% risk reduction) and significantly improved progression-free survival.