NAV

Sacituzumab govitecan

Identification

Summary

Sacituzumab govitecan is sacituzumab govitecan targets TROP-2-expressing cancer cells through a humanized antibody (RS7) before subsequently becoming internalized and releasing the topoisomerase I inhibitor SN-38 to induce DNA damage-mediated apoptosis.

Brand Names
Trodelvy
Generic Name
Sacituzumab govitecan
DrugBank Accession Number
DB12893
Background

Metastatic triple-negative breast cancer (mTNBC) is an aggressive form of breast cancer with limited treatment options involving cytotoxic chemotherapy agents.1 Targeted chemotherapy through the application of antibody-conjugated agents (ADCs) is a recent advance in cancer treatment.7 One such ADC is sacituzumab govitecan, which combines a humanized anti-trophoblast cell-surface antigen 2 (TROP-2) antibody with the topoisomerase I inhibitor SN-38.10,8

Sacituzumab govitecan was granted FDA approval on April 22nd, 2020 and is marketed under the brand name Trodelvy™ by Immunomedics, Inc.; it is currently indicated under accelerated approval for the treatment of mTNBC patients who have undergone two or more prior therapies. As a targeted cytotoxic agent, it is hoped to provide similar efficacy with reduced adverse effects.1 In November 2021 and July 20 2023, sacituzumab govitecan was also approved by the European Commission and Health Canada respectively.11,14

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
Not Available
Protein Average Weight
Not Available
Sequences
Not Available
Synonyms
  • Sacituzumab govitecan
  • sacituzumab govitecan-hziy
External IDs
  • hRS 7SN38
  • hRS7-SN38
  • IMMU 132
  • IMMU-132
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Pharmacology

Indication

Sacituzumab govitecan is indicated for adult patients with unresectable locally-advanced or metastatic triple-negative breast cancer (mTNBC) who have undergone two or more prior therapies for metastatic disease by the FDA, Health Canada, and EMA.12,13,15 It is also indicated for the treatment of unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting.12,13,15 These indications are approved in the US, Canada, and Europe.

In the US, sacituzumab govitecan is additionally indicated for the treatment of locally advanced or metastatic urothelial cancer in adult patients who have received previous platinum-based therapy and either a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor. This indication has been approved under accelerated approval, and continued approval may be contingent on the demonstration of clinical benefit in confirmatory trials.10

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofHormone receptor positive metastatic breast cancer•••••••••••••••••••••• ••••••••• •••••••• •• ••••• •••••••• ••••••••••••••••••• ••••••• •••••••••••• ••• ••••••••
Treatment ofLocally advanced or metastatic urothelial carcinoma (uc)••••••••••••••••••••••••• ••••••• •••• •••••••••• ••••• •••••••••• •••••• •• •••••••••• •••••••••••• • ••••••• •••••••••• •••••••• •••••••• ••••• ••••••••••••••••
Treatment ofMetastatic triple negative breast cancers••••••••••••••••••• ••••• •••••••• ••••••••••••••••••• ••••••• •••••••••••• ••• ••••••••
Treatment ofMetastatic triple negative breast cancers••••••••••••••••••• ••••• •••••••• ••••••••••••••••••
Treatment ofMetastatic triple-negative breast cancer••••••••••••••••••••••••• •••••••••• •••••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Sacituzumab govitecan is a humanized monoclonal antibody/topoisomerase inhibitor conjugate designed to induce DNA damage-mediated cell death preferentially in TROP-2-expressing cancer cells. Detailed pharmacodynamic studies have not been performed for sacituzumab govitecan, although as a therapeutic protein, there is potential for immunogenicity. In addition, sacituzumab govitecan has the potential to cause severe hypersensitivity, nausea and vomiting, and embryo-fetal toxicity. Patients who are homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia.10

Mechanism of action

Sacituzumab govitecan is an antibody-drug conjugate (ADC) targeting TROP-2-expressing cancer cells to induce DNA-damage-mediated cell death. The conjugate comprises a humanized anti-TROP-2 monoclonal antibody (RS7-3G11, also known as RS7) chemically linked by a hydrolyzable CL2A linker to the cytotoxic drug SN-38.10,4

The proposed mechanism of action first involves the binding of the RS7 component to TROP-2, which is highly expressed on the cell surface of multiple cancers.7 Binding of RS7 to TROP-2 results in rapid internalization of bound antibody2,3, and the likely intracellular release of SN-38 via hydrolysis of the CL2A linker10,8. SN-38 is an active metabolite of the anti-cancer drug irinotecan, which is thought to work primarily through inhibition of DNA topoisomerase I, leading to DNA damage and eventual cell death.5 In addition, recent work has identified a possible secondary mechanism of action for SN-38 by disrupting the binding of Far Upstream Binding Protein 1 (FUBP1) to the FUSE elements regulating oncogene expression.6

In addition to SN-38-mediated cell death, there is also some evidence that the RS7 component of the conjugate drug possesses antibody-directed cellular toxicity.8,4

TargetActionsOrganism
ATumor-associated calcium signal transducer 2
antibody
Humans
ADNA topoisomerase 1
inhibitor
Humans
UFar upstream element-binding protein 1
inhibitor
Humans
Absorption

In patients receiving 10 mg/kg sacituzumab govitecan the Cmax of the conjugate was 243,000 ± 45,600 ng/mL while the Cmax of free SN-38 was 127 ± 60 ng/mL. Similarly, the AUC0-168 for the conjugate/free SN-38 was 5,210,000 ± 1,230,000 and 3,900 ± 1,830 ng*h/mL, respectively.10

Volume of distribution

Sacituzumab govitecan has a mean volume of distribution of 0.045 L/kg.10

Protein binding

SN-38, the active moiety, remains mostly bound to the IgG component in serum. In patients administered with 10 mg/kg of sacituzumab govitecan, free SN-38 serum levels were measured as 2.3% and 4.5% at 30 minutes and one day, respectively.9

Metabolism

The metabolism of sacituzumab govitecan has not been extensively studied. The SN-38 moiety is known to undergo O-glucuronidation by UGT1A1, presumably in the liver, and the SN-38 glucuronide metabolite SN-38G is found in the serum of patients undergoing treatment.10,5

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Route of elimination

No detailed information exists for sacituzumab govitecan elimination; renal elimination of SN-38 is known to be minimal, and it is expected that the fecal route will be the major contributor.10,5

Half-life

Sacituzumab govitecan has a mean half-life of 16 hours, while free SN-38 has a mean half-life of 18 hours.10,9

Clearance

Sacituzumab govitecan has a clearance rate of 0.002 L/h/kg.10

Adverse Effects
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Toxicity

Toxicity information regarding sacituzumab govitecan is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as neutropenia, diarrhea, hypersensitivity, nausea/vomiting, and other systemic effects related to cytotoxic drugs. Symptomatic and supportive measures are recommended.10

Pathways
Not Available
Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
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interactions in your software
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Sacituzumab govitecan.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Sacituzumab govitecan.
AdenineThe serum concentration of Sacituzumab govitecan can be increased when it is combined with Adenine.
AducanumabThe risk or severity of adverse effects can be increased when Aducanumab is combined with Sacituzumab govitecan.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Sacituzumab govitecan.
Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TrodelvyPowder, for solution180 mg / vialIntravenousGilead Sciences2021-11-22Not applicableCanada flag
TrodelvyPowder, for solution180 mg/1IntravenousGilead Sciences2020-04-22Not applicableUS flag
TrodelvyInjection, powder, for solution200 mgIntravenousGilead Sciences Ireland Uc2022-05-04Not applicableEU flag

Categories

ATC Codes
L01FX17 — Sacituzumab govitecan
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
M9BYU8XDQ6
CAS number
1491917-83-9

References

Synthesis Reference

Cardillo TM, Govindan SV, Sharkey RM, Trisal P, Goldenberg DM: Humanized anti-Trop-2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: preclinical studies in human cancer xenograft models and monkeys. Clin Cancer Res. 2011 May 15;17(10):3157-69. doi: 10.1158/1078-0432.CCR-10-2939. Epub 2011 Mar 3.

General References
  1. Zangardi ML, Spring LM, Nagayama A, Bardia A: Sacituzumab for the treatment of triple-negative breast cancer: the poster child of future therapy? Expert Opin Investig Drugs. 2019 Feb;28(2):107-112. doi: 10.1080/13543784.2019.1555239. Epub 2018 Dec 17. [Article]
  2. Stein R, Basu A, Chen S, Shih LB, Goldenberg DM: Specificity and properties of MAb RS7-3G11 and the antigen defined by this pancarcinoma monoclonal antibody. Int J Cancer. 1993 Dec 2;55(6):938-46. doi: 10.1002/ijc.2910550611. [Article]
  3. Shih LB, Xuan H, Aninipot R, Stein R, Goldenberg DM: In vitro and in vivo reactivity of an internalizing antibody, RS7, with human breast cancer. Cancer Res. 1995 Dec 1;55(23 Suppl):5857s-5863s. [Article]
  4. Goldenberg DM, Stein R, Sharkey RM: The emergence of trophoblast cell-surface antigen 2 (TROP-2) as a novel cancer target. Oncotarget. 2018 Jun 22;9(48):28989-29006. doi: 10.18632/oncotarget.25615. eCollection 2018 Jun 22. [Article]
  5. Bailly C: Irinotecan: 25 years of cancer treatment. Pharmacol Res. 2019 Oct;148:104398. doi: 10.1016/j.phrs.2019.104398. Epub 2019 Aug 12. [Article]
  6. Khageh Hosseini S, Kolterer S, Steiner M, von Manstein V, Gerlach K, Trojan J, Waidmann O, Zeuzem S, Schulze JO, Hahn S, Steinhilber D, Gatterdam V, Tampe R, Biondi RM, Proschak E, Zornig M: Camptothecin and its analog SN-38, the active metabolite of irinotecan, inhibit binding of the transcriptional regulator and oncoprotein FUBP1 to its DNA target sequence FUSE. Biochem Pharmacol. 2017 Dec 15;146:53-62. doi: 10.1016/j.bcp.2017.10.003. Epub 2017 Oct 13. [Article]
  7. Ponde N, Aftimos P, Piccart M: Antibody-Drug Conjugates in Breast Cancer: a Comprehensive Review. Curr Treat Options Oncol. 2019 Apr 1;20(5):37. doi: 10.1007/s11864-019-0633-6. [Article]
  8. Cardillo TM, Govindan SV, Sharkey RM, Trisal P, Goldenberg DM: Humanized anti-Trop-2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: preclinical studies in human cancer xenograft models and monkeys. Clin Cancer Res. 2011 May 15;17(10):3157-69. doi: 10.1158/1078-0432.CCR-10-2939. Epub 2011 Mar 3. [Article]
  9. Ocean AJ, Starodub AN, Bardia A, Vahdat LT, Isakoff SJ, Guarino M, Messersmith WA, Picozzi VJ, Mayer IA, Wegener WA, Maliakal P, Govindan SV, Sharkey RM, Goldenberg DM: 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. [Article]
  10. FDA Approved Drug Products: Trodelvy (sacituzumab govitecan-hziy) injection [Link]
  11. BioSpace News Release: Trodelvy® (sacituzumab govitecan) Granted European Commission Marketing Authorization for Treatment of Metastatic Triple-Negative Breast Cancer in Second Line [Link]
  12. FDA Approved Drug Products: Trodelvy (sacituzumab govitecan-hziy) for intravenous injection (February 2023) [Link]
  13. Health Canada Approved Drug Proucts: TRODELVY (sacituzumab govitecan) lyophilized powder for solution for injection, for intravenous use [Link]
  14. HEALTH CANADA APPROVES TRODELVY® (SACITUZUMAB GOVITECAN) IN PRE-TREATED HR+/HER2- METASTATIC BREAST CANCER [Link]
  15. EMA Approved Drug Products: Trodelvy (sacituzumab govitecan) for intravenous injection [Link]
PubChem Substance
347911403
RxNav
2360232
Wikipedia
Sacituzumab_govitecan
FDA label
Download (792 KB)

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
PhaseStatusPurposeConditionsCount
4Enrolling by InvitationTreatmentMetastatic Solid Neoplasm1
3Active Not RecruitingTreatmentLocally Advanced or Metastatic Unresectable Urothelial Cancer1
3Active Not RecruitingTreatmentMetastatic Breast Cancer1
3Active Not RecruitingTreatmentNon-Small Cell Lung Cancer (NSCLC)1
3CompletedTreatmentBreast Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous200 mg
Powder, for solutionIntravenous180 mg / vial
Powder, for solutionIntravenous180 mg/1
InjectionParenteral200 mg
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Targets

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Details1. Tumor-associated calcium signal transducer 2
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antibody
Curator comments
The RS7 monoclonal antibody component of sacituzumab govitecan binds to TROP-2, allowing for the conjugate to be internalized into target cells.
General Function
May function as a growth factor receptor.
Specific Function
Not Available
Gene Name
TACSTD2
Uniprot ID
P09758
Uniprot Name
Tumor-associated calcium signal transducer 2
Molecular Weight
35709.02 Da
References
  1. Cardillo TM, Govindan SV, Sharkey RM, Trisal P, Goldenberg DM: Humanized anti-Trop-2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: preclinical studies in human cancer xenograft models and monkeys. Clin Cancer Res. 2011 May 15;17(10):3157-69. doi: 10.1158/1078-0432.CCR-10-2939. Epub 2011 Mar 3. [Article]
  2. FDA Approved Drug Products: Trodelvy (sacituzumab govitecan-hziy) injection [Link]
Details2. DNA topoisomerase 1
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
SN-38-mediated inhibition of DNA topoisomerase I is thought to be the main mechanism of action.
General Function
Poly(a) rna binding
Specific Function
Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a singl...
Gene Name
TOP1
Uniprot ID
P11387
Uniprot Name
DNA topoisomerase 1
Molecular Weight
90725.19 Da
References
  1. Bailly C: Irinotecan: 25 years of cancer treatment. Pharmacol Res. 2019 Oct;148:104398. doi: 10.1016/j.phrs.2019.104398. Epub 2019 Aug 12. [Article]
  2. FDA Approved Drug Products: Trodelvy (sacituzumab govitecan-hziy) injection [Link]
Details3. Far upstream element-binding protein 1
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
The clinical relevance of FUBP1 inhibition is currently not known.
General Function
Transcriptional activator activity, rna polymerase ii distal enhancer sequence-specific binding
Specific Function
Regulates MYC expression by binding to a single-stranded far-upstream element (FUSE) upstream of the MYC promoter. May act both as activator and repressor of transcription.
Gene Name
FUBP1
Uniprot ID
Q96AE4
Uniprot Name
Far upstream element-binding protein 1
Molecular Weight
67560.205 Da
References
  1. Khageh Hosseini S, Kolterer S, Steiner M, von Manstein V, Gerlach K, Trojan J, Waidmann O, Zeuzem S, Schulze JO, Hahn S, Steinhilber D, Gatterdam V, Tampe R, Biondi RM, Proschak E, Zornig M: Camptothecin and its analog SN-38, the active metabolite of irinotecan, inhibit binding of the transcriptional regulator and oncoprotein FUBP1 to its DNA target sequence FUSE. Biochem Pharmacol. 2017 Dec 15;146:53-62. doi: 10.1016/j.bcp.2017.10.003. Epub 2017 Oct 13. [Article]

Enzymes

Details1. UDP-glucuronosyltransferase 1-1
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da
References
  1. FDA Approved Drug Products: Trodelvy (sacituzumab govitecan-hziy) injection [Link]

Drug created at October 21, 2016 01:04 / Updated at August 19, 2023 10:38