UGT1A1 status and clinical outcomes in pancreatic cancer patients receiving liposomal irinotecan.

Abstract

e16429 Background: Pancreatic cancer (PCa) is one of the most lethal malignancies with limited effective treatment options. Liposomal irinotecan (nal-IRI) in combination with 5-fluorouracil/leucovorin ± oxaliplatin is utilized across multiple PCa disease stages. Nal-IRI is metabolized to its active form SN-38, which is inactivated by the UGT1A1 enzyme. UGT1A1 gene polymorphisms decrease enzyme activity, potentially increasing toxicity. While UGT1A1 polymorphisms are known to impact conventional irinotecan toxicity, and the NAPOLI-1 trial protocol included reduced starting doses of nal-IRI for UGT1A1*28 homozygotes, subsequent studies of liposomal irinotecan show conflicting results. Real-world data examining UGT1A1 status and outcomes in diverse US populations is limited. This study evaluates the relationship between UGT1A1 metabolizer status and clinical outcomes in patients (pts) treated with nal-IRI-based regimens. Methods: This retrospective study analyzed 86 pts with PCa who received nal-IRI at Ochsner Health between September 2020 and January 2025. UGT1A1 genotypes were classified as normal (NMT), intermediate (IMT), or poor metabolizers (PMT). Outcomes included grade 3/4 toxicities, dose reductions, and overall and progression free survival. Chi-square tests compared proportions of toxicities and dose reductions across groups. Kaplan-Meier curves with log-rank tests and Cox regression models analyzed survival. Results: Of 86 pts reviewed (mean age 69 years, 51% female, 67% White, 31% Black), 85 had metastatic disease and 57 (66%) had a documented UGT1A1 status. 24 (42%) were NMT, 23 (40%) were IMT and 10 (18%) were PMT. The median nal-IRI starting dose for pts with NMT and IMT was 70 mg/m2. 90% of PMT patients received reduced starting doses, with a median initial dose of 50mg/m2. Subsequent dose reductions occurred in 33% NMT, 22% IMT, and 30% PMT (p = 0.67). Grade 3/4 toxicities were observed in 37.5% NMT and 42% IMT/PMT, with diarrhea (28%) and neutropenia (9%) being most common. Mortality rates at data cutoff were 79% NMT, 87% IMT, and 90% PMT (p = 0.71). There were no significant overall survival differences between metabolizer groups (PMT vs NMT: HR 1.32, 95% CI 0.56-2.90; IMT vs NMT: HR 1.77, 95% CI 0.92-3.42). Conclusions: Consistent with existing guideline recommendations, most pts in our analysis were treated with nal-IRI at a reduced starting dose of 50 mg/m2. Otherwise, UGT1A1 metabolizer status was not significantly associated with severe toxicities, dose reductions, or survival in pts receiving nal-IRI. Whether these findings suggest that the liposomal formulation may attenuate the genotype-associated toxicity seen with conventional irinotecan or reflect lower starting doses, they cannot be determined from this study's limited, retrospective data. Larger prospective studies are needed to determine whether UGT1A1 testing should guide nal-IRI dosing in practice.