Impact of UGT1A1*28 polymorphism in patients with metastatic pancreatic ductal adenocarcinoma treated with NALIRIFOX in the NAPOLI 3 trial

Document Type

Article

Publication Date

5-1-2026

Publication Title

Future Oncol

Keywords

Humans, Glucuronosyltransferase, UGT1A1 Enzyme, Carcinoma, Pancreatic Ductal, Antineoplastic Combined Chemotherapy Protocols, Pancreatic Neoplasms, Irinotecan, Female, Male, Aged, Fluorouracil, Leucovorin, Middle Aged, Oxaliplatin, Adult, Genotype, Polymorphism, Genetic, Paclitaxel

Abstract

AIMS: To evaluate the effect of UGT1A1*28 homozygosity on the safety profile of NALIRIFOX (liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) in NAPOLI 3 (NCT04083235). METHODS: This pre-specified exploratory analysis evaluated safety outcomes by UGT1A1*28 status in patients with mPDAC receiving NALIRIFOX or gemcitabine plus nab-paclitaxel in NAPOLI 3. All patients receiving NALIRIFOX initiated liposomal irinotecan at the full starting dose. RESULTS: Among 749 treated patients, 83 were homozygous for UGT1A1*28. In the NALIRIFOX arm, grade ≥3 and serious treatment-emergent adverse events (TEAEs) related to liposomal irinotecan occurred in 61.5% and 33.3% of patients with homozygous UGT1A1*28 (n = 39), respectively, compared with 63.7% and 22.9% of patients with other genotypes (n = 328). The most common any-grade TEAEs for NALIRIFOX were diarrhea (59.0%), nausea (56.4%), vomiting (46.2%), and anemia (41.0%) in the homozygous group and diarrhea (71.6%), nausea (59.8%), vomiting (38.4%), and decreased appetite (38.1%) in the other genotypes group. Rates of TEAE-related treatment discontinuation and dose reduction/interruption in the NALIRIFOX arm were similar across genotypes. CONCLUSIONS: UGT1A1*28 homozygosity was not associated with increased toxicity in patients receiving NALIRIFOX in NAPOLI 3. These findings support the use of full NALIRIFOX dosing irrespective of UGT1A1*28 status. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT04083235; EudraCT 2018-003585-14.

Medical Subject Headings

Humans; Glucuronosyltransferase; UGT1A1 Enzyme; Carcinoma, Pancreatic Ductal; Antineoplastic Combined Chemotherapy Protocols; Pancreatic Neoplasms; Irinotecan; Female; Male; Aged; Fluorouracil; Leucovorin; Middle Aged; Oxaliplatin; Adult; Genotype; Polymorphism, Genetic; Paclitaxel

PubMed ID

42080361

Volume

22

Issue

12

First Page

1421

Last Page

1428

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