Case report of sacituzumab govitecan-hziy-induced neutropenia in a patient with metastatic triple-negative breast cancer and a uridine diphosphate glucuronosyltransferase family 1 member A1 poor metabolizer genotype

Abstract

Introduction Sacituzumab govitecan-hziy, approved in 2020 for treatment of metastatic triple-negative breast cancer, provides a new option for a population with a historically poor prognosis with standard chemotherapy. Uridine diphosphate glucuronosyltransferase family 1 member A1 poor metabolizers are at increased risk for profound neutropenia. This case discusses clinical implications of the uridine diphosphate glucuronosyltransferase family 1 member A1*28/*28 genotype in patients receiving sacituzumab govitecan-hziy. Case report A 38-year-old otherwise healthy pre-menopausal female of South Asian descent was diagnosed with non-metastatic, hormone receptor-positive, and human epidermal growth factor receptor 2-negative breast cancer. This was treated with neoadjuvant chemotherapy and multiple lines of subsequent therapies. Upon finding bone metastasis, an additional six lines of therapy ensued. In total, 3.5 years post-diagnosis, sacituzumab govitecan-hziy was started for disease transformation to triple-negative status. Management and outcome Sacituzumab govitecan-hziy was initiated at the Food and Drug Administration-approved 10 mg/kg/dose on days 1 and 8 of a 21-day cycle. Grade 4 neutropenia occurred after one dose. Pharmacogenomics testing identified the patient as a uridine diphosphate glucuronosyltransferase family 1 member A1*28 homozygous expressor. Sacituzumab govitecan-hziy was dose-reduced, and granulocyte colony-stimulating factor was administered due to the severity of neutropenia. The patient continued on sacituzumab govitecan-hziy until disease progression. Discussion Sacituzumab govitecan-hziy's propensity to cause neutropenia is multifactorial. Although incidence of all-grade neutropenia from sacituzumab govitecan-hziy is elevated for uridine diphosphate glucuronosyltransferase family 1 member A1*28 homozygous expressors, this does not translate to increased risk for febrile neutropenia. Detailed guidance is lacking regarding empiric dose adjustments or prophylactic granulocyte colony-stimulating factor for these patients. 1 Currently, pre-sacituzumab govitecan-hziy pharmacogenomics testing to identify uridine diphosphate glucuronosyltransferase family 1 member A1 poor metabolizers is not recommended, and the cost-effectiveness of this approach is unclear.

A New Kid on the Block: Sacituzumab Govitecan for the Treatment of Breast Cancer and Other Solid Tumors

“…Thanks to their unique pharmacological proprieties, third-generation ADCs are an extremely promising class of drugs on the landscape of anticancer treatment [ 1 , 42 , 52 ]. Indeed, SG represents an emerging therapeutic option for cancer patients who historically exhibit a dismal prognosis and limited treatment options, such as those presenting with TNBC and urothelial carcinomas [ 35 , 53 ].…”

“…The activity of this enzyme can be reduced in up to 20% of the Black or African American subjects and 10% of the White subjects due to the presence of allele gene variants, such as UGT1A1*28 [ 41 ]. Subjects harboring this specific variant may present an increased risk of SG-induced toxicity, especially neutropenia, and should be closely monitored [ 42 ]. However, UGT1A1 genotyping is not routinely recommended before starting SG [ 41 ].…”

Antibody drug conjugates: Design implications for clinicians

“…Off-target mechanisms include nonspecific uptake of sacituzumab govitecan and bystander killing, with increased risk in UDP-1A1*28 homozygous expressors. 43 Bystander killing occurs when the small-molecule payload from an ADC is released within the target cell and diffuses out to adjacent cells or is released in the extracellular space, affecting nearby cells that may or may not have the ADC target antigen. 44 The bystander killing effect of sacituzumab govitecan is driven by its cleavable linker and hydrophobicity of the attached small-molecule payload.…”

Current Therapeutic Strategies for Metastatic Triple-Negative Breast Cancer: From Pharmacists’ Perspective

“…(4) When patients first develop grade 4 neutropenia for a minimum 7-day duration or grade 3 febrile neutropenia, a 25% reduction in sacituzumab govitecan dose and administration of G-CSF is recommended in the prescribing information released by the FDA [ 69 ]. However, the evidence for prophylactic use of G-CSF is very limited and preliminary prophylactic use is not recommended [ 70 ]. (5) Evidence suggests an increased risk of adverse reactions in patients with the UGT1A1*28 variant genotype.…”

“…The appropriate dose for these patients is unknown. Therefore, it is necessary to explore whether there is a minimum threshold for dose reduction in patients with UGT1A1*28 purex, thereby reducing toxicity [ 70 ].…”