Sacituzumab govitecan
Monoclonal antibody
TypeWhole antibody
SourceHumanized (from mouse)
TargetTrop-2
Clinical data
Trade namesTrodelvy
Other namesIMMU-132, hRS7-SN-38, sacituzumab govitecan-hziy
AHFS/Drugs.comMonograph
MedlinePlusa620034
License data
Pregnancy
category
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC76H104N12O24S
Molar mass1601.79 g·mol−1
3D model (JSmol)
  • CCC1=C2CN3C(=CC4=C(C3=O)COC(=O)C4(CC)OC(=O)OCC5=CC=C(C=C5)NC(=O)C(CCCCN)NC(=O)COCC(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCN6C=C(N=N6)CNC(=O)C7CCC(CC7)CN8C(=O)CC(C8=O)SCC(C(=O)O)N)C2=NC9=C1C=C(C=C9)O
  • InChI=1S/C76H104N12O24S/c1-3-55-56-37-54(89)16-17-61(56)83-68-57(55)43-87-63(68)38-59-58(71(87)95)45-110-74(99)76(59,4-2)112-75(100)111-44-50-10-14-52(15-11-50)81-70(94)62(7-5-6-18-77)82-66(91)47-109-46-65(90)79-19-21-101-23-25-103-27-29-105-31-33-107-35-36-108-34-32-106-30-28-104-26-24-102-22-20-86-42-53(84-85-86)40-80-69(93)51-12-8-49(9-13-51)41-88-67(92)39-64(72(88)96)113-48-60(78)73(97)98/h10-11,14-17,37-38,42,49,51,60,62,64,89H,3-9,12-13,18-36,39-41,43-48,77-78H2,1-2H3,(H,79,90)(H,80,93)(H,81,94)(H,82,91)(H,97,98)/t49?,51?,60-,62-,64?,76-/m0/s1
  • Key:ULRUOUDIQPERIJ-PQURJYPBSA-N

Sacituzumab govitecan, sold under the brand name Trodelvy, is a Trop-2-directed antibody and topoisomerase inhibitor drug conjugate used for the treatment of metastatic triple-negative breast cancer and metastatic urothelial cancer.[9][11][12][13]

The most common side effects include nausea, neutropenia, diarrhea, fatigue, anemia, vomiting, alopecia (hair loss), constipation, decreased appetite, rash and abdominal pain.[12][13][14] Sacituzumab govitecan has a boxed warning about the risk of severe neutropenia (abnormally low levels of white blood cells) and severe diarrhea.[12][13] Sacituzumab govitecan may cause harm to a developing fetus or newborn baby.[12]

Sacituzumab govitecan was approved for medical use in the United States in April 2020,[12][13][15] and in the European Union in November 2021.[10] The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) consider it to be a first-in-class medication.[16][17]

Medical uses

Sacituzumab govitecan is indicated for the treatment of adults with metastatic triple-negative breast cancer who received at least two prior therapies for metastatic disease;[11] people with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease;[14] and for people with locally advanced or metastatic urothelial cancer (mUC) who previously received a platinum-containing chemotherapy and either a programmed death receptor-1 (PD-1) or a programmed death-ligand 1 (PD-L1) inhibitor.[18]

It is also indicated for the treatment of people with unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting.[19]

Mechanism

Sacituzumab govitecan is a conjugate of the humanized anti-Trop-2 monoclonal antibody linked with SN-38, the active metabolite of irinotecan.[20] Each antibody having on average 7.6 molecules of SN-38 attached.[21] Linkage to an antibody allows the drug to specifically target cells expressing Trop-2.

Sacituzumab govitecan is a Trop-2-directed antibody and topoisomerase inhibitor drug conjugate, meaning that the drug targets the Trop-2 receptor that helps the cancer grow, divide and spread, and is linked to topoisomerase inhibitor, which is a chemical compound that is toxic to cancer cells.[12] Approximately two of every ten breast cancer diagnoses worldwide are triple-negative.[12] Triple-negative breast cancer is a type of breast cancer that tests negative for estrogen receptors, progesterone receptors and human epidermal growth factor receptor 2 (HER2) protein.[12] Therefore, triple-negative breast cancer does not respond to hormonal therapy medicines or medicines that target HER2.[12]

Development

Immunomedics announced in 2013, that it had received fast track designation from the US Food and Drug Administration (FDA) for the compound as a potential treatment for non-small cell lung cancer, small cell lung cancer, and metastatic triple-negative breast cancer. Orphan drug status was granted for small cell lung cancer and pancreatic cancer.[22][23] In February 2016, Immunomedics announced that sacituzumab govitecan had received an FDA breakthrough therapy designation (a classification designed to expedite the development and review of drugs that are intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition) for the treatment of people with triple-negative breast cancer who have failed at least two other prior therapies for metastatic disease.[24][25]

History

Sacituzumab govitecan was added to the proposed International nonproprietary name (INN) list in 2015,[26] and to the recommended list in 2016.[27]

Sacituzumab govitecan-hziy was approved for medical use in the United States in April 2020.[12][13][14][28][11]

Sacituzumab govitecan-hziy was approved based on the results of IMMU-132-01, a multicenter, single-arm clinical trial (NCT01631552) of 108 participants with metastatic triple-negative breast cancer who had received at least two prior treatments for metastatic disease.[12][11][13] Of the 108 participants involved within the study, 107 were female and 1 was male.[29] Participants received sacituzumab govitecan-hziy at a dose of 10 milligrams per kilogram of body weight intravenously on days one and eight every 21 days.[11][29] Treatment with sacituzumab govitecan-hziy was continued until disease progression or unacceptable toxicity.[29] Tumor imaging was obtained every eight weeks.[11][13] The efficacy of sacituzumab govitecan-hziy was based on the overall response rate (ORR) – which reflects the percentage of participants that had a certain amount of tumor shrinkage.[12][11] The ORR was 33.3% (95% confidence interval [CI], 24.6 to 43.1).[12][11][29] Additionally, with the 33.3% of study participants who achieved a response, 2.8% of participants experienced complete responses.[29] The median time to response in participants was 2.0 months (range, 1.6 to 13.5), the median duration of response was 7.7 months (95% confidence interval [CI], 4.9 to 10.8), the median progression free survival was 5.5 months, and the median overall survival was 13.0 months.[29] Of the participants that achieved an objective response to sacituzumab govitecan-hziy, 55.6% maintained their response for six or more months and 16.7% maintained their response for twelve or more months.[12][11]

Sacituzumab govitecan-hziy was granted accelerated approval along with priority review, breakthrough therapy, and fast track designations.[12][11][14] The U.S. Food and Drug Administration (FDA) granted approval of Trodelvy to Immunomedics, Inc.[12]

In April 2021, the FDA granted regular approval to sacituzumab govitecan for people with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease.[14] Efficacy and safety were evaluated in a multicenter, open-label, randomized trial (ASCENT; NCT02574455) conducted in 529 participants with unresectable locally advanced or mTNBC who had relapsed after at least two prior chemotherapies, one of which could be in the neoadjuvant or adjuvant setting, if progression occurred within twelve months.[14] Participants were randomized (1:1) to receive sacituzumab govitecan, 10 mg/kg as an intravenous infusion, on days 1 and 8 of a 21-day (n=267) cycle or physician's choice of single agent chemotherapy (n=262).[14]

In April 2021, the FDA granted accelerated approval to sacituzumab govitecan for people with locally advanced or metastatic urothelial cancer (mUC) who previously received a platinum-containing chemotherapy and either a programmed death receptor-1 (PD-1) or a programmed death-ligand 1 (PD-L1) inhibitor.[18] Efficacy and safety were evaluated in TROPHY (IMMU-132-06; NCT03547973), a single-arm, multicenter trial that enrolled 112 participants with locally advanced or mUC who received prior treatment with a platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor.[18]

In February 2023, the FDA approved sacituzumab govitecan for people with unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting.[19][30][31]

Society and culture

Legal status

On 14 October 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Trodelvy, intended for the treatment of unresectable or metastatic triple-negative breast cancer.[17][32] The applicant for this medicinal product is Gilead Sciences Ireland UC.[32] Sacituzumab govitecan was approved for medical use in the European Union in November 2021.[10][33]

References

  1. ^ a b "Trodelvy". Therapeutic Goods Administration (TGA). 14 September 2021. Archived from the original on 17 September 2021. Retrieved 17 September 2021.
  2. ^ "Updates to the Prescribing Medicines in Pregnancy database". Therapeutic Goods Administration (TGA). 12 May 2022. Archived from the original on 3 April 2022. Retrieved 13 May 2022.
  3. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  4. ^ "Trodelvy sacituzumab govitecan 180 mg powder for injection vial". Therapeutic Goods Administration (TGA). Archived from the original on 17 September 2021. Retrieved 17 September 2021.
  5. ^ "TGA eBS - Product and Consumer Medicine Information Licence". Archived from the original on 22 February 2022. Retrieved 22 February 2022.
  6. ^ "AusPAR: Sacituzumab govitecan | Therapeutic Goods Administration (TGA)". Archived from the original on 24 November 2022. Retrieved 24 November 2022.
  7. ^ "Trodelvy | Therapeutic Goods Administration (TGA)". Archived from the original on 24 November 2022. Retrieved 24 November 2022.
  8. ^ "Summary Basis of Decision (SBD) for Trodelvy". Health Canada. 23 October 2014. Archived from the original on 29 May 2022. Retrieved 29 May 2022.
  9. ^ a b "Trodelvy- sacituzumab govitecan powder, for solution". DailyMed. Archived from the original on 20 March 2021. Retrieved 9 April 2021.
  10. ^ a b c "Trodelvy EPAR". European Medicines Agency. 14 September 2021. Archived from the original on 25 November 2021. Retrieved 24 November 2021.
  11. ^ a b c d e f g h i j "FDA grants accelerated approval to sacituzumab govitecan-hziy for metastatic triple negative breast cancer". U.S. Food and Drug Administration (FDA). 22 April 2020. Archived from the original on 23 April 2020. Retrieved 23 April 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  12. ^ a b c d e f g h i j k l m n o p "FDA Approves New Therapy for Triple Negative Breast Cancer That Has Spread, Not Responded to Other Treatments". U.S. Food and Drug Administration (FDA). 22 April 2020. Archived from the original on 23 April 2020. Retrieved 22 April 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  13. ^ a b c d e f g "Drug Trial Snapshot: Trodelvy". U.S. Food and Drug Administration (FDA). 22 April 2020. Archived from the original on 30 April 2020. Retrieved 29 April 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  14. ^ a b c d e f g "FDA grants regular approval to sacituzumab govitecan for TNBC". U.S. Food and Drug Administration (FDA). 8 April 2021. Archived from the original on 8 April 2021. Retrieved 9 April 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  15. ^ "Drug Approval Package: Trodelvy". U.S. Food and Drug Administration (FDA). 19 May 2020. Archived from the original on 20 October 2021. Retrieved 10 February 2023.
  16. ^ "New Drug Therapy Approvals 2020". U.S. Food and Drug Administration (FDA). 31 December 2020. Archived from the original on 18 January 2021. Retrieved 17 January 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  17. ^ a b "First-in-class medicine to treat aggressive form of breast cancer". European Medicines Agency (Press release). 15 October 2021. Archived from the original on 15 October 2021. Retrieved 15 October 2021.
  18. ^ a b c "FDA grants accelerated approval to sacituzumab govitecan for advanced urothelial cancer". U.S. Food and Drug Administration (FDA). 13 April 2021. Archived from the original on 13 April 2021. Retrieved 13 April 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  19. ^ a b "FDA approves sacituzumab govitecan-hziy for HR-positive breast cancer". FDA. 3 February 2023. Archived from the original on 9 February 2023. Retrieved 9 February 2023. Public Domain This article incorporates text from this source, which is in the public domain.
  20. ^ Cardillo TM, Govindan SV, Sharkey RM, Trisal P, Arrojo R, Liu D, et al. (May 2015). "Sacituzumab Govitecan (IMMU-132), an Anti-Trop-2/SN-38 Antibody-Drug Conjugate: Characterization and Efficacy in Pancreatic, Gastric, and Other Cancers". Bioconjugate Chemistry. 26 (5): 919–931. doi:10.1021/acs.bioconjchem.5b00223. PMID 25915780.
  21. ^ "Novel Agents are Targeting Drivers of TNBC". www.medpagetoday.com. 28 June 2016. Archived from the original on 13 June 2021. Retrieved 12 June 2019.
  22. ^ "Sacituzumab govitecan Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). 24 December 1999. Archived from the original on 24 June 2021. Retrieved 22 April 2020.
  23. ^ "Sacituzumab govitecan Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). 24 December 1999. Archived from the original on 2 July 2020. Retrieved 22 April 2020.
  24. ^ "New Therapy Shows Early Promise, Continues to Progress in Triple-Negative Breast Cancer". Cure Today. Archived from the original on 22 December 2019. Retrieved 12 June 2019.
  25. ^ "U.S. Food and Drug Administration (FDA) Grants Breakthrough Therapy Designation to Immunomedics for Sacituzumab Govitecan for the Treatment of Patients With Triple-Negative Breast Cancer" (Press release). Immunomedics. 5 February 2016. Archived from the original on 25 April 2020. Retrieved 25 April 2020 – via GlobeNewswire.
  26. ^ World Health Organization (2015). "International nonproprietary names for pharmaceutical substances (INN): proposed INN: list 113". WHO Drug Information. 29 (2): 260–1. hdl:10665/331080.
  27. ^ World Health Organization (2016). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 75". WHO Drug Information. 30 (1): 151–3. hdl:10665/331046.
  28. ^ "Trodelvy: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Archived from the original on 28 July 2020. Retrieved 22 April 2020.
  29. ^ a b c d e f Bardia A, Mayer IA, Vahdat LT, Tolaney SM, Isakoff SJ, Diamond JR, et al. (February 2019). "Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer". The New England Journal of Medicine. 380 (8): 741–751. doi:10.1056/NEJMoa1814213. PMID 30786188. S2CID 73489970.
  30. ^ "FDA Approves Trodelvy for HER2-Negative, HR-Positive Metastatic Breast Cancer". Cure Today. 3 February 2023. Archived from the original on 9 February 2023. Retrieved 9 February 2023.
  31. ^ "U.S. FDA Approves Trodelvy in Pre-treated HR+/HER2- Metastatic Breast Cancer". Gilead (Press release). Archived from the original on 9 February 2023. Retrieved 9 February 2023.
  32. ^ a b "Trodelvy: Pending EC decision". European Medicines Agency. 15 October 2021. Archived from the original on 18 October 2021. Retrieved 15 October 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  33. ^ "Trodelvy Product information". Union Register of medicinal products. Retrieved 3 March 2023.

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