Sacituzumab Govitecan-hziy

Sacituzumab govitecan-hziy (Trodelvy) is an antibody-drug conjugate composed of a humanized monoclonal antibody targeting Trophoblast cell-surface antigen 2 (Trop-2) linked to SN-38, the active metabolite of irinotecan.

It is approved for the treatment of adults with metastatic triple-negative breast cancer and urothelial carcinoma who have received at least two prior therapies. The antibody binds to Trop-2 on tumor cells, is internalized, and releases SN-38, which inhibits topoisomerase I, leading to DNA damage and cancer cell death.

The primary gene involved in the metabolism of sacituzumab govitecan-hziy is UGT1A1. UGT1A1 encodes the enzyme UDP-glucuronosyltransferase 1A1, which catalyzes the glucuronidation of SN-38 into an inactive, water-soluble form (SN-38G) for excretion.

Genetic variations in UGT1A1 that reduce or eliminate enzyme activity can lead to higher circulating levels of SN-38. This may increase the risk of treatment-related toxicities, such as neutropenia and diarrhea.

Patients with reduced UGT1A1 function (intermediate or poor metabolizers) clear SN-38 more slowly, leading to higher systemic exposure and an increased risk of severe neutropenia and diarrhea. Normal metabolizers typically tolerate standard dosing, while the impact for those with indeterminate results is unknown.

Normal Metabolizer

• Effect on drug levels: Normal clearance of SN-38
• Clinical consequence: Standard efficacy and toxicity profile
• Side effects: Typical risk of neutropenia and diarrhea as seen in clinical trials (moderate frequency)

Intermediate Metabolizer

• Effect on drug levels: Moderately reduced clearance of SN-38
• Clinical consequence: Increased exposure may lead to higher toxicity
• Side effects: Elevated risk of neutropenia and diarrhea (higher frequency and severity than normal)

Poor Metabolizer

• Effect on drug levels: Significantly reduced clearance of SN-38
• Clinical consequence: Markedly increased risk of severe neutropenia and diarrhea
• Side effects: High risk of severe neutropenia (potentially life-threatening) and severe diarrhea

Indeterminate/Not Available

• Effect on drug levels: Unknown
• Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring

UGT1A1 Dosing Guideline

The FDA guidance does not specify any alternative therapies or dosing adjustments beyond standard recommendations. Clinicians may consider other treatment regimens based on patient tolerance and response.

• FDA – Table of Pharmacogenetic Associations