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Background and Importance UGT1A1 genotype-guided dosing significantly reduces the incidence of severe toxicity in UGT1A1 poor metabolizer (PM) patients treated with irinotecan (Hulshof et al. Eur J Cancer 2022). However, the impact of UGT1A1 genotype-guided irinotecan dosing on survival outcomes remains unknown.Aim and Objectives This study evaluated whether upfront 30% dose reductions of irinotecan in UGT1A1 PMs affect survival by comparing progression-free (PFS) and overall survival (OS) between PMs treated with an initial 30% dose-reduction and fully dosed intermediate and normal metabolizers (IM/NMs).Materials and Methods We conducted a retrospective, multicentre cohort study in patients with pancreatic cancer (PC) or colorectal cancer (CRC) treated with UGT1A1 genotype-guided irinotecan dosing at six Dutch hospitals between Aug 2017–Apr 2024. Patients were included in the primary analysis if irinotecan was dosed according to UGT1A1 genotype (i.e. 100%±10% dose intensity for IM/NMs and 70%±10% for PMs) in at least cycle 1. Survival analyses were performed using Kaplan-Meier estimates and multivariable Cox regressions, stratified by tumor type. Safety was also assessed.Results In total, 779 patients were included in the primary analysis, 76 (9.8%) of whom were PMs. PFS and OS rates were comparable over time between PMs and IM/NMs (stratified log-rank test: PFS: P = 0.542; OS: P = 0.419) (figure 1). For patients with PC, median PFS was 9.0 months (95%CI: 6.2-11.8) in PMs and 8.3 months (95%CI: 7.2-9.4) in IM/NMs. For patients with CRC, median PFS was 6.2 months (95%CI: 5.1-7.3) in PMs and 6.0 months (95%CI: 5.3-6.7) in IM/NMs. Median OS was not statistically significant between PMs and IM/NMs. The adjusted hazard ratio of PMs vs IM/NMs was 1.015 (95%CI: 0.78-1.32; P = 0.90) for PFS and was 1.10 (95%CI: 0.82-1.48; P = 0.51) for OS, indicating no significant differences in survival outcomes between 30% dose-reduced PMs and fully dosed IM/NMs. Severe toxicity rates were comparable between PMs and IM/NMs.Abstract NP-012 Figure 1Carbon footprint savings achieved by delivering outpatient medications to community pharmaciesConclusion and Relevance Survival of UGT1A1 poor metabolizers is not affected by an upfront 30% dose reduction of irinotecan. Therefore, UGT1A1 genotype-guided dosing of irinotecan can be confidently performed and should become the new standard-of-care dosing strategy for irinotecan to improve patient safety.