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

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.