Overview of Clinical Trial Data

Clinical Trial Evidence for Treatment Decisions

First-line treatment recommendations for metastatic pancreatic adenocarcinoma are founded on pivotal randomized phase 3 trials that have established the current therapeutic landscape. The PRODIGE4 trial represented a landmark study comparing FOLFIRINOX with single-agent gemcitabine, which was the standard of care at that time. This trial enrolled treatment-naive patients with metastatic pancreatic cancer aged up to 75 years with good performance status (ECOG 0-1) and bilirubin levels up to 1.5 times the upper limit of normal. FOLFIRINOX demonstrated a superior median overall survival of 11.1 months compared with 6.8 months with gemcitabine, alongside a higher overall response rate of 32%. However, this efficacy came with significant high-grade toxicity, including neutropenia (46%), febrile neutropenia (5%), neuropathy (9%), and diarrhea (13%).

The IMPACT trial subsequently evaluated gemcitabine plus nab-paclitaxel against single-agent gemcitabine, demonstrating improved survival (8.5 vs 6.7 months) with more manageable toxicity profiles, including neutropenia (38%) and neuropathy (17%). Following these foundational trials, the assumption that 3-drug regimens were superior to 2-drug combinations had never been formally tested until the NAPOLI-3 trial. This groundbreaking study directly compared NALIRIFOX (containing liposomal irinotecan at 50 mg/m², oxaliplatin at 60 mg/m², and infusional 5-FU without bolus) with the established gemcitabine plus nab-paclitaxel standard.

The NAPOLI-3 trial enrolled over 750 patients across 18 countries and 180 sites, including community centers representing real-world patient populations. This superiority-designed trial demonstrated improved median overall survival with NALIRIFOX (11.1 months) compared with gemcitabine plus nab-paclitaxel (9.2 months). Notably, the toxicity profile favored NALIRIFOX, with less high-grade myelosuppression and neuropathy compared with the control arm, although NALIRIFOX showed higher rates of high-grade diarrhea (20%) and nausea (12%). These results led to FDA approval and established NALIRIFOX as a new standard-of-care option for appropriately selected patients.