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UGT1A1 and Sacituzumab Govitecan Toxicity: A Systematic Review and Meta-Analysis.
Cinzia Dello Russo1,2, Innocent Gerald Asiimwe3, Sudeep Pushpakom1,4
1Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
Clinical Pharmacology and Therapeutics
|September 12, 2025
Summary
Individuals with the UGT1A1*28/*28 genotype face higher risks of severe toxicity from sacituzumab govitecan (SG). Pre-treatment genetic screening can guide personalized dosing and monitoring for these patients.
Area of Science:
- Pharmacogenomics
- Oncology
- Clinical Pharmacology
Background:
- Sacituzumab govitecan (SG) delivers SN-38 for enhanced efficacy but shares toxicity profiles with irinotecan.
- SN-38 inactivation by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) is influenced by genetic variations, potentially leading to toxicity.
Purpose of the Study:
- To systematically review and meta-analyze the impact of UGT1A1 genotype on sacituzumab govitecan toxicity.
- To determine if UGT1A1 genotype is a predictor of SG-related adverse events.
Main Methods:
- A systematic review and meta-analysis (PROSPERO ID: CRD42024598820) of studies investigating UGT1A1 genotype and SG toxicity.
- Included four clinical trials with 999 genotyped subjects, assessing odds ratios (ORs) with 95% Confidence Intervals (CIs) for various genotypes compared to wild-type.
- Risk of bias was evaluated using the STROPS guideline.
Main Results:
- UGT1A1*28 homozygous subjects showed increased risk for neutropenia (OR: 1.80), anemia (OR: 1.62), and severe toxicities (OR: 7.03) with low heterogeneity.
- A higher likelihood of dose reductions and treatment interruptions was observed in UGT1A*28 homozygous individuals.
- Diarrhea risk was also elevated, though not statistically significant (OR: 1.38).
Conclusions:
- Individuals with the UGT1A*28/*28 genotype are at significantly increased risk of severe sacituzumab govitecan-related toxicity.
- Pre-treatment UGT1A1 genotyping is recommended to identify patients who may benefit from personalized dosing strategies, enhanced monitoring, or alternative treatments.
