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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.
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.
Insights
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.
