Impact of UGT1A1∗28 polymorphism on tolerability in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with NALIRIFOX in NAPOLI 3
Recommended Citation
Abdelrahim M, Khan G, Hatoum H, Zervoudakis A, Dayyani F, Zhang L, Li J, Maxwell F, O'Reilly EM, Wainberg ZA, Peters ML. Impact of UGT1A1∗28 polymorphism on tolerability in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with NALIRIFOX in NAPOLI 3. 2025; (4_Suppl):717.
Document Type
Conference Proceeding
Publication Date
5-28-2025
Abstract
Background: SN-38, the active metabolite of irinotecan, is cleared by the liver enzyme uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and biliary excretion. UGT1A1∗28 (genotype 7/7) homozygosity is associated with reduced activity of UGT1A1 and a recommendation for dose adjustment of non-liposomal irinotecan, a component of the FOLFIRINOX regimen. In this post-hoc analysis, we analyzed the impact of UGT1A1∗28 homozygosity on the incidence and profile of treatment-emergent adverse events (TEAEs) among patients enrolled in NAPOLI 3 (NCT04083235). Methods: Patients (N = 770) with confirmed untreated mPDAC were randomized (1:1) to receive liposomal irinotecan 50 mg/m2 + oxaliplatin 60 mg/m2 + leucovorin 400 mg/m2 + 5-fluorouracil 2400 mg/m2 (NALIRIFOX) on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 (Gem+NabP) on days 1, 8 and 15 of a 28-day cycle. UGT1A1∗28 status was evaluated in all patients before enrollment. All patients, regardless of UGT1A1∗28 status, received the full starting dose of liposomal irinotecan and followed the same dose reduction rules. This exploratory analysis of TEAEs by UGT1A1∗28 status was descriptive; statistical analyses were not performed. Results: Overall, 83 patients (11.0%) were homozygous for UGT1A1∗28, among whom the incidence of TEAEs was similar to patients with non-homozygous status (Table). The most frequently reported TEAEs (≥ 40%) among the homozygous group (vs the overall NAPOLI 3 population) were diarrhea (59.0% vs 70.5%), nausea (56.4% vs 59.5%), vomiting (46.2% vs 39.7%) and anemia (41.0% vs 26.2%) in the NALIRIFOX arm and nausea (45.5% vs 42.7%), fatigue (45.5% vs 37.7%), diarrhea (45.5% vs 36.7%) and anemia (40.9% vs 40.4%) in the Gem+NabP arm. Conclusions: The incidence of TEAEs, including TEAEs leading to death, was similar between patients with homozygous and non-homozygous UGT1A1∗28 status, in both treatment arms. The profile of TEAEs was consistent with that of the overall NAPOLI 3 population. UGT1A1∗28 status did not substantially influence the safety profile or subsequent need for dose reductions of liposomal irinotecan in NAPOLI 3. (Table Presented).
Issue
4_Suppl
First Page
717
