UGT1A1 and Sacituzumab Govitecan Toxicity: A Systematic Review and Meta-Analysis.

Abstract

Sacituzumab govitecan (SG), a humanized antibody-drug conjugate, enables intra-tumor delivery of SN-38, the active metabolite of irinotecan, with the aim of increasing efficacy. SN-38 is predominantly inactivated by the polymorphically expressed uridine diphosphate glucuronosyltransferase 1A1 (UGT1AA) where reduced activity can lead to toxicity. SG toxicity closely resembles that of irinotecan. We conducted a systematic review and meta-analysis (PROSPERO ID: CRD42024598820) to assess UGT1A1 genotype as a determinant of SG toxicity. Studies published up to September 29, 2024, on UGT1A1 genotype and SG toxicity were eligible. Risk of bias was assessed using the STROPS guideline. Effect estimates for each genotype, comparing heterozygotes and homozygotes to wild-type, were analyzed. Odds ratios (ORs) with 95% Confidence Intervals (CIs) and forest plots were generated for each exposure-outcome combination. Four clinical trials including 999 UGT1A1 genotyped subjects were selected for the meta-analysis. SG treatment in UGT1A1*28 homozygous subjects increased the risk of toxicity. The OR (95% CI) was 1.80 (1.03-3.14) for neutropenia, 1.38 (0.90-2.10) for diarrhea, and 1.62 (1.07-2.45) for anemia of any grade, with low heterogeneity (I² ≤ 28%). The OR for all severe (grade ≥ 3) toxicities combined was 7.03 (95% CI: 3.41-14.50, I² = 18%). UGT1A*28 homozygous subjects were more likely to have dose reductions and treatment interruptions compared to wild-type individuals. In conclusion, individuals with UGT1A*28/*28 genotype are at an increased risk of severe SG-related toxicity. Pre-treatment genotyping should be used to identify individuals that may benefit from personalized dosing, closer monitoring or alternative therapies.