Analyses of the NAPOLI-3 Trial

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Two important abstracts presented at the 2025 American Society of Clinical Oncology Gastrointestinal Cancers Symposium provided crucial insights into NALIRIFOX (liposomal irinotecan, 5-fluorouracil, leucovorin, oxaliplatin) management and genetic considerations. The first analysis examined dose adjustment effects on overall survival in patients with metastatic pancreatic adenocarcinoma from the NAPOLI-3 trial (NCT04083235). Results confirmed that diarrhea represented the most common adverse event, leading to dose reductions of both nanoliposomal irinotecan and oxaliplatin (40% and 36%, respectively). Notably, North American patients experienced higher rates of diarrhea (≥grade 3) requiring dose reduction (38%) compared with the rest of the world (24%).

Among patients not requiring dose reductions, disease progression was the primary reason for treatment discontinuation (38%), with adverse events accounting for approximately 20% of discontinuations. Crucially, this post hoc analysis demonstrated that dose adjustments for toxicity management did not adversely affect overall survival outcomes. This finding provides reassurance that appropriate toxicity management, including dose modifications when necessary, does not compromise treatment efficacy as long as patients continue to benefit and tumors respond to therapy.

The second analysis investigated the impact of UGT1A1 mutations on NALIRIFOX outcomes, examining the homozygous UGT1A1*28 genotype 7/7 mutation that reduces enzyme activity for clearing SN-38 (irinotecan’s active metabolite). Approximately 11% of patients in NAPOLI-3 were homozygous for this mutation, but treatment-emergent adverse events were similar between mutated and wild-type patients. The similar toxicity profiles likely result from nanoliposomal irinotecan’s already reduced starting dose of 50 mg/m² compared with conventional irinotecan, suggesting routine UGT1A1 testing may not be necessary for NALIRIFOX administration, unlike conventional irinotecan-containing regimens.