Impact of <i>UGT1A1*28</i> polymorphism on tolerability in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with NALIRIFOX in NAPOLI 3.

717 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/m 2 + oxaliplatin 60 mg/m 2 + leucovorin 400 mg/m 2 + 5-fluorouracil 2400 mg/m 2 (NALIRIFOX) on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m 2 and gemcitabine 1000 mg/m 2 (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. Clinical trial information: NCT04083235 . UGT1A1*28 homozygous UGT1A1*28 non-homozygous TEAE, n (%) NALIRIFOX (n = 39) Gem+NabP (n = 44) NALIRIFOX (n = 328) Gem+NabP (n = 331) Any 39 (100.0) 44 (100.0) 327 (99.7) 328 (99.1) Related to any drug 39 (100.0) 41 (93.2) 310 (94.5) 308 (93.1) Grade ≥ 3 31 (79.5) 34 (77.3) 288 (87.8) 288 (87.0) Serious 24 (61.5) 24 (54.5) 176 (53.7) 168 (50.8) Leading to treatment discontinuation 15 (38.5) 10 (22.7) 103 (31.4) 100 (30.2) Leading to dose reduction of any drug 23 (59.0) 14 (31.8) 182 (55.5) 174 (52.6) Leading to interruption of any drug 1 (2.6) 1 (2.3) 15 (4.6) 3 (0.9) Leading to death 2 (5.1) 4 (9.1) 20 (6.1) 19 (5.7)