mPDAC Frontline Therapy: Real-World Evidence and Emerging Trial Data From ASCO 2025

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The toxicity profile differences between NALIRIFOX and modified FOLFIRINOX significantly impact treatment selection and patient counseling in pancreatic cancer management. NALIRIFOX’s reduced oxaliplatin dose (50 mg/m² vs 85 mg/m² in FOLFIRINOX) substantially decreases peripheral neuropathy risk, making it particularly attractive for patients with baseline neuropathy or those concerned about long-term neurological adverse effects. However, the liposomal irinotecan formulation in NALIRIFOX tends to cause more diarrhea due to prolonged circulation time, requiring enhanced patient education about proactive diarrhea management.

Neutropenia rates favor NALIRIFOX when compared with gemcitabine/nab-paclitaxel in the NAPOLI-3 trial, though direct comparison with FOLFIRINOX remains limited. Growth factor support is commonly used with both regimens, though insurance coverage limitations increasingly affect treatment decisions in real-world practice. The UGT1A1 enzyme polymorphism, crucial for irinotecan metabolism, affects approximately 10% to 12% of patients, but NAPOLI-3 data suggest routine testing may be unnecessary given the modified dosing approach already employed.

Clinical practice generally doesn’t require up-front UGT1A1 testing due to the extended turnaround time and the modified dosing strategy already incorporated in NALIRIFOX. The reduced-dose approach in NALIRIFOX appears to provide adequate safety margins even for patients with UGT1A1 polymorphisms, with toxicity management based on observed tolerability rather than preemptive genetic testing. This practical approach simplifies treatment initiation while maintaining safety profiles comparable to those of standard dosing strategies.