Is there any literature to guide dosing of sacituzumab in patients that are UGT1A1 poor or intermediate metabolizers?

Comment by InpharmD Researcher

There appears to be no consensus on a well-established dosing strategy for sacituzumab in patients who are UGT1A1 poor or intermediate metabolizers. Routine genotyping is not recommended prior to starting sacituzumab and the cost-effectiveness of this approach is unclear. Patients with reduced UGT1A1 activity may require close monitoring. Empiric dosing adjustments should be approached on a case-by-case basis. A phase I/II study demonstrated no significant correlation between the 3 haplotypes (*28*28/*1*28/*1*1) and severe neutropenia for the combined 8 mg/kg and 10 mg/kg groups occurring within the first 2 cycles or at any time during treatment or for patients who only received 10 mg/kg. An assignment of likely UGT1A1 phenotypes based on genotypes is summarized in Table 1.

Background

Clinical Pharmacogenetics Implementation Consortium (CPIC) does not provide specific dosing guidelines for sacituzumab based on patients’ genotypes. [1]

A recent 2021 review summarized the management of patients receiving sacituzumab govitecan for metastatic triple-negative breast cancer. The review reported a lack of metabolism studies conducted with sacituzumab but stated that genetic variants of the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) gene, including the UGT1A1*28 allele, lead to reduced UGT1A1 enzyme activity. Patients who are homozygous for UGT1A1*28 were at an increased risk of neutropenia associated with sacituzumab. Manufacturer's data suggest that approximately 20% of the Black or African American population, 10% of the White population, and 2% of the East Asian population may be affected. Based on UGT1A1 genotype results, the incidence of grade 4 neutropenia was 26% in patients homozygous for the UGT1A1*28 allele, 13% in patients heterozygous for the UGT1A1*28 allele, and 11% in patients homozygous for the wild-type allele. Routine genotyping was not recommended prior to starting sacituzumab, but patients who are known to have reduced UGT1A1 activity required close monitoring. The authors suggested dosing for patients homozygous for the UGT1A1*28 alleles must be approached on a case-by-case basis, as there is currently no well-defined dosing strategy. [2]

References:

[1] Clinical Pharmacogenetics Implementation Consortium (CPIC). PHARMGKB. Sacituzumab govitecan-hziy. Available
https://www.pharmgkb.org/chemical/PA166225061/overview. Accessed March 9, 2022.

[2] Spring LM, Nakajima E, Hutchinson J, et al. Sacituzumab Govitecan for Metastatic Triple-Negative Breast Cancer: Clinical Overview and Management of Potential Toxicities. Oncologist. 2021;26(10):827-834. doi:10.1002/onco.13878
Relevant Prescribing Information

Pharmacogenomics [3]
SN-38 is metabolized via UGT1A1. Genetic variants of the UGT1A1 gene such as the UGT1A1*28 allele lead to reduced UGT1A1 enzyme activity. Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia from TRODELVY. Approximately 20% of the Black or African American population, 10% of the White population, and 2% of the East Asian population are homozygous for the UGT1A1*28 allele. Decreased function alleles other than UGT1A1*28 may be present in certain populations.

Warnings and precautions
Increased Risk of Adverse Reactions in Patients with Reduced UGT1A1 Activity:
Patients homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia; and may be at increased risk for other adverse reactions when treated with TRODELVY.

The incidence of neutropenia and anemia was analyzed in 701 patients who received TRODELVY and had UGT1A1 genotype results. In patients homozygous for the UGT1A1 *28 allele (n= 87), the incidence of Grade 3–4 neutropenia was 67%. In patients heterozygous for the UGT1A1*28 allele (n= 301), the incidence of Grade 3–4 neutropenia was 46%. In patients homozygous for the wild-type allele (n= 313), the incidence of Grade 3–4 neutropenia was 46%. In patients homozygous for the UGT1A1 *28 allele, the incidence of Grade 3–4 anemia was 25%. In patients heterozygous for the UGT1A1*28 allele, the incidence of Grade 3–4 anemia was 10%. In patients homozygous for the wild-type allele, the incidence of Grade 3–4 anemia was 11%.

Closely monitor patients with known reduced UGT1A1 activity for adverse reactions. Withhold or permanently discontinue TRODELVY based on clinical assessment of the onset, duration and severity of the observed adverse reactions in patients with evidence of acute early-onset or unusually severe adverse reactions, which may indicate reduced UGT1A1 enzyme activity.

References:

[3] Sacituzumab (Troveldy) [prescribing information]. Morris Plains, NJ: Gilead Sciences, Inc.; 2021.
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Is there any literature to guide dosing of sacituzumab in patients that are UGT1A1 poor or intermediate metabolizers?

Level of evidence

D - Case reports or unreliable data  Read more→


Please see Tables 1-3 for your response.

Assignment of likely UGT1A1 phenotypes based on genotypes
Likely phenotype Genotypes  Examples of diplotypes 
Extensive metabolizer

An individual carrying two referenceb function (*1)c and/or increased function alleles (*36). 

Alternatively identified by homozygosity for rs887829 C/C.

 *1/*1; *1/*36; *36/*36; rs887829 C/C
Intermediate metabolizer

An individual carrying one referenceb function (*1)c or increased function allele (*36) plus one decreased function allele (*6, *28, *37).

Alternatively identified by heterozygosity for rs887829 C/T.

 *1/*28; *1/*37; *36/*28; *36/*37; rs887829 C/T, *1/*6
Poor metabolizer

An individual carrying two decreased function alleles (*6, *28, *37).

Alternatively identified by homozygosity for rs887829 T/T (*80/*80)

 *28/*28; *28/*37; *37/*37; rs887829 T/T (*80/*80), *6/*6a
aHomozygosity for UGT1A1*6, which occurs almost exclusively in individuals of Asian descent, is associated with Gilbert's syndrome. However, at this time it is unclear if patients with this diplotype are at increased risk of severe atazanavir‐associated hyperbilirubinemia.
b“Reference” function refers to the UGT1A1 alleles to which other alleles are compared.
cThe reference function *1 allele is fully functional and refers to the rs8175347 TA6 allele.
References:

Adopted from:
Gammal RS, Court MH, Haidar CE, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for UGT1A1 and Atazanavir Prescribing. Clin Pharmacol Ther. 2016;99(4):363-369. doi:10.1002/cpt.269

 

Sacituzumab Govitecan (IMMU-132), an Anti-Trop-2-SN-38 Antibody-Drug Conjugate for the Treatment of Diverse Epithelial Cancers: Safety and Pharmacokinetics

Design

Multi-center, single-arm, phase I/II clinical trial

N= 178

Objective

To examine the pharmacokinetics and safety of multiple cycles of IMMU-132 at doses of 8 or 10 mg/kg in patients with diverse advanced epithelial cancers

Study Groups

Sacituzumab 8 mg/kg (n= 81)

Sacituzumab 10 mg/kg (n= 97)

Inclusion Criteria

Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1; adequate hematologic, liver, and renal function (grade ≤ 1 according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events [CTCAE], version 4.03)

Exclusion Criteria

Pregnancy, Gilbert disease, intolerance to previous irinotecan-containing therapy, known central nervous system metastases (unless stable for at least 4 weeks), or any single lesion > 7 cm in the greatest dimension

Methods

Enrollment was performed sequentially, first at the 8 mg/kg dose level and then at 10 mg/kg level. All treatments were given by intravenous infusion at an initial infusion rate of 50 mg/hour and completed within 3 hours. Premedications (e.g., diphenhydramine, acetaminophen, and dexamethasone) were administered to reduce the risk of infusion reactions. Antiemetics and anticholinergics (e.g., atropine sulfate) were permitted at the physician’s discretion.

Treatments were given with cycles repeated until progression or intolerance. If adverse events grade ≥ 3 occurred, dosing was delayed, with or without subsequent reductions. Response rate follow-up was performed every 8 weeks unless there was more than a 30% reduction in the sum of the greatest dimension of the target lesion. A baseline uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) was evaluated by gel electrophoresis.  

Duration

April 30, 2015, through June 30, 2015

Outcome Measures

Objective response rate, grade ≥ 3 adverse events

Baseline Characteristics

  

All patients (N= 178)

 

  

Median age (range), years

 62 (33 to 88)    

Female

110 (62%)    

ECOG Performance status

0

1

 

53 (30%)

125 (70%)

    

Prior treatments

Median No. (range)

Received ≥ 3 Lines:

 

4 (1 to 11)

124 (70%) 

    

Sacituzumab starting dose

8 mg/kg 

10 mg/kg 

 

81 (46%)

97 (54%)

    

Available UGT1A1 status 

8 mg/kg (n= 81)

10 mg/kg (n= 97)

146 (82%)

69 (39%)

44 (25%)

    

Baseline UGT1A1 status

*28*28

*1*28

*1*1

 

19 (13%)

64 (44%)

63 (43%)

    

Results

Endpoint

8 mg/kg (n= 81)

10 mg/kg (n= 97)

 

Objective response rate*

(n= 50)

5 (10%)

(n= 68)

15 (22%)

  

Grade ≥ 3 adverse events

Neutrophil count decrease

Anemia

Diarrhea

Febrile neutropenia

White blood cell decrease

(n= 80)

24 (30%)

10 (13%)

3 (4%)

3 (4%)

5 (6%)

(n= 89)

32 (36%)

11 (12%)

9 (10%)

6 (7%)

11 (12%)

  

*Except for colorectal cancer

Although there was a significant correlation between the haplotypes and grade 3 diarrhea for all patients (p= 0.024), there was no significant correlation when only patients in the 10 mg/kg group were examined (p= 0.357).

The patients’ UGT1A1 status was not a useful predictor of severe diarrhea, and 84% of patients with higher risk *28*28 UGT1A1 haplotype had grade ≤ 2 diarrhea.

There was no significant correlation between the 3 haplotypes and severe neutropenia for the combined dose groups occurring within the first 2 cycles or at any time during treatment (p= 0.073 and p= 0.278, respectively) or for patients who only received 10 mg/kg (p= 0.9927 and p= 0.872, respectively).

Adverse Events

 Refer to the results section

Study Author Conclusions

In conclusion, the current clinical results in patients with diverse metastatic solid cancers continue to indicate that sacituzumab govitecan is safe and has a therapeutic activity in several metastatic solid cancer types, even after many prior lines of therapy. Sacituzumab govitecan has an excellent PK profile with a low fraction of SN-38G, resulting in lower rates of diarrhea and a manageable toxicity profile. 

InpharmD Researcher Critique

This study was a non-randomized, phase I/II trial, and the results are only used to perform further investigations. The patients’ UGT1A1 status was not a useful predictor of grade ≥ 3 adverse reactions, and the need for dose adjustment in patients with poor or intermediate UGT1A1 metabolism remains uncertain.



References:

Ocean AJ, Starodub AN, et al. Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate for the treatment of diverse epithelial cancers: Safety and pharmacokinetics. Cancer. 2017 Oct 1;123(19):3843-3854. doi: 10.1002/cncr.30789. Epub 2017 May 30. PMID: 28558150.

 

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

Design

Case report 

Case presentation

A 38-year-old pre-menopausal female of South Asian descent with no prior comorbidities presented with a right breast mass and nipple inversion, leading to the diagnosis of invasive carcinoma of the right breast. Pathology demonstrated estrogen receptor (ER)-positive/progesterone receptor (PR)-positive and human epidermal growth factor receptor 2 (HER2)-negative disease with Ki-67 of 30%. There was no evidence of metastatic disease beyond the breast and locoregional lymph nodes. Unfortunately, after neoadjuvant chemotherapy, mastectomy, axillary lymph node dissection, and radiation followed by endocrine therapy, her disease later progressed to invasive carcinoma with a primary site of the right breast and the subsequently received six lines of therapy in the metastatic setting, all ultimately discontinued due to tumor progression. Pathology from a lung biopsy at the time of tumor progression indicated transformation to triple-negative breast cancer (ER/PR/ HER2-negative). 

Consequently, sacituzumab govitecan-hziy (SG) was initiated at the FDA-approved dose of 10 mg/kg/day on days 1 and 8 of a 21-day cycle. As the absolute neutrophil count (ANC) was 0.23 cells/mL was noticed on day 8 of cycle 1, treatment was held and UGT1A1 pharmacogenomics (PGx) testing later showed UGT1A1*28/*28 genotype. Despite daily filgrastim-sdnz for secondary neutropenia prophylaxis, three days later the patient became febrile to 101.4 °F (38.6 °C). She denied diarrhea or other adverse effects at that time. Due to the above complications, the SG dose was reduced by 25% and prophylactic G-CSF was maintained for cycle 2 onward. Repeated neutrophils counts remained above 1 cell/mL; however, the tumor progressed with a total of 11 cycles of SG. The patient went on hospice and eventually passed 1 month after the last dose of SG.

Study Author Conclusions

Sacituzumab govitecan-hziy’s propensity to cause neutropenia is multifactorial. Although the 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. 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.
References:

Baek G, Jung L, Duong A, Gralow J. 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. Journal of Oncology Pharmacy Practice. 2021:107815522110574. doi:10.1177/10781552211057486