Sacituzumab govitecan (IMMU‐132), an anti‐Trop‐2‐SN‐38 antibody‐drug conjugate for the treatment of diverse epithelial cancers: Safety and pharmacokinetics

Ocean, Allyson J.; Starodub, Alexander; Bardia, Aditya; Vahdat, Linda T.; Isakoff, Steven J.; Guarino, Michael J.; Messersmith, Wells A.; Picozzi, Vincent J.; Mayer, Ingrid A.; Wegener, William A.; Maliakal, Pius; Govindan, Serengulam V.; Sharkey, Robert M.; Goldenberg, David M.

doi:10.1002/cncr.30789

Cited by 175 publications

(206 citation statements)

References 33 publications

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“…14 It is a biomarker for sacituzumab govitecan, an antibody-drug conjugate. 14,30 In this ADC, the anti-Trop-2 antibody (hRS7) serves as a mode of delivery for SN-38, the active metabolite of irinotecan, an inhibitor of topoisomerase-1. 14,30 Of note, topoisomerase-1 overexpression has been previously reported in approximately 40% of breast NECs.…”

Section: Biomarkers Expressionmentioning

confidence: 99%

“…14,30 In this ADC, the anti-Trop-2 antibody (hRS7) serves as a mode of delivery for SN-38, the active metabolite of irinotecan, an inhibitor of topoisomerase-1. 14,30 Of note, topoisomerase-1 overexpression has been previously reported in approximately 40% of breast NECs. 3 In addition, a recent phase II trial showed durable therapeutic responses induced by sacituzumab govitecan in patients with heavily pretreated and metastatic triple-negative breast cancers.…”

Section: Biomarkers Expressionmentioning

confidence: 99%

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Potential Novel Therapy Targets in Neuroendocrine Carcinomas of the Breast

Vranić

Palazzo

Sanati

et al. 2019

Clinical Breast Cancer

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Neuroendocrine breast cancer lacks specific therapy, but similar common neuroendocrine carcinomas may offer guidance for therapy development. This study, for the first time, identified several biomarkers for targeted therapy approaches in patients with breast neuroendocrine carcinoma. Introduction: Neuroendocrine carcinoma (NEC) of the breast is a rare, special type of breast cancer, reportedly constituting 2% to 5% of all breast cancers. Although breast NEC does not have a specific targeted therapy, several new targeted therapies based on specific biomarkers were recently investigated in the NEC of lung and in other types of breast carcinoma, which may provide guidance to their feasibility in breast NEC. Materials and Methods: Twenty breast NECs were profiled for biomarkers of therapy including antibody-drug conjugates (DLL3, TROP-2, and FOLR1), histone deacetylase (H3K36Me3) inhibitors, tropomyosin receptor kinases (NTRK1/2/3 gene fusions) targeted inhibitors, alkylating agents (MGMT), and immune checkpoint inhibitors (PD-L1, TMB, and MSI) using immunohistochemistry and DNA/RNA next-generation sequencing assays. Results: Predictive expression of TROP-2, FOLR1, and H3K36Me3 were detected in different subsets of tumors and may pave the way for development of novel targeted therapies in some patients with breast NECs. There was no evidence of DLL3 expression, NTRK gene fusions, or MGMT hypermethylation. No biomarkers predictive of immune checkpoint inhibitor efficacy (programmed death-ligand 1 expression, tumor mutational burden, microsatellite instability) were identified. FGFR and CCND1 gene amplifications were detected in isolated cases. Conclusions: This study identified several potential targets for novel therapies in breast NEC, including farletuzumab and mirvetuximab soravtansine (FOLR1), sacituzumab govitecan (TROP-2), and HDAC inhibitors (H3K36Me3). In some cases, CCND1 gene amplification may indicate the usefulness of investigational therapies. The reported results should serve as an early indication of potential clinical relevance in selected patients with breast NEC.

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Section: Biomarkers Expressionmentioning

confidence: 99%

Section: Biomarkers Expressionmentioning

confidence: 99%

Potential Novel Therapy Targets in Neuroendocrine Carcinomas of the Breast

Vranić

Palazzo

Sanati

et al. 2019

Clinical Breast Cancer

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“…The recently approved trastuzumab deruxtecan (Enhertu™) employs exatecan, a synthetic derivative of the topoisomerase I inhibitor camptothecin [103], as a payload (Figure 2d). Another camptothecin derivative, SN-38, is an active metabolite of anticancer drug irinotecan and used in e.g., sacituzumab govitecan [120]. Camptothecin is an alkaloid isolated from the plant Camptotheca acuminate and potently inhibits the growth of cancer cells with nanomolar IC 50 [121].…”

Section: Cytotoxic Drugsmentioning

confidence: 99%

Bispecific Antibodies and Antibody–Drug Conjugates for Cancer Therapy: Technological Considerations

Shim

2020

Biomolecules

104

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The ability of monoclonal antibodies to specifically bind a target antigen and neutralize or stimulate its activity is the basis for the rapid growth and development of the therapeutic antibody field. In recent years, traditional immunoglobulin antibodies have been further engineered for better efficacy and safety, and technological developments in the field enabled the design and production of engineered antibodies capable of mediating therapeutic functions hitherto unattainable by conventional antibody formats. Representative of this newer generation of therapeutic antibody formats are bispecific antibodies and antibody–drug conjugates, each with several approved drugs and dozens more in the clinical development phase. In this review, the technological principles and challenges of bispecific antibodies and antibody–drug conjugates are discussed, with emphasis on clinically validated formats but also including recent developments in the fields, many of which are expected to significantly augment the current therapeutic arsenal against cancer and other diseases with unmet medical needs.

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“…Sacituzumab govitecan is another ADC, composed of SN‐38—a potent active metabolite of irinotecan—conjugated to a humanized monoclonal antibody against Trop‐2, which is a transmembrane calcium signal transducer, implicated in tumor progression, that is expressed in ≥50% of all TNBCs . In the initial IMMU‐132‐01 phase I/II study, 69 heavily pretreated mTNBC patients (median of five prior therapies; range, 1‐12) were treated by SG at a dose of 10 mg/kg on days 1 and 8 of 21‐day repeated cycles .…”

Section: Exploring Genetic Events To Tailor Therapy Of Mtnbcmentioning

confidence: 99%

Personalized treatment in metastatic triple‐negative breast cancer: The outlook in 2020

et al. 2019

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Compared with other breast cancer subtypes, patients with triple‐negative breast cancer (TNBC), and irrespective to their disease stage, were always recognized to have the worst overall survival data. Although this does not seem different at the present time, yet the last few years have witnessed many breakthrough genomic and molecular findings, that could dramatically improve our understanding of the biological complexity of TNBC. Based on genomic analyses, it was consistently evident that TNBC comprises a heterogeneous group of cancers, which have numerous diverse molecular aberrations. This—in return—has provided a platform for a new generation of clinical trials using many innovative therapies, directed against such novel targets. At the present time, two PARP inhibitors and one anti‐PD‐L1 monoclonal antibody (in combination with chemotherapy) have been approved in certain subpopulations of metastatic TNBC (mTNBC) patients, which have finally brought this disease into the era of personalized medicine. In the current review, we will explore the genomic landscape of TNBC, through which many actionable targets were graduated. We will also discuss the results of the key—practice changing—clinical studies, and some upcoming personalized treatment options for patients with mTNBC, that may be clinically adopted in the near future.

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Sacituzumab govitecan (IMMU‐132), an anti‐Trop‐2‐SN‐38 antibody‐drug conjugate for the treatment of diverse epithelial cancers: Safety and pharmacokinetics

Abstract: Sacituzumab govitecan has a predictable pharmacokinetic profile and manageable toxicity at doses of 8 and 10 mg/kg. With objective responses and a good therapeutic index at 10 mg/kg, this dose was chosen for future development. Cancer 2017;123:3843-3854. © 2017 American Cancer Society.

Cited by 175 publications

References 33 publications

Potential Novel Therapy Targets in Neuroendocrine Carcinomas of the Breast

Potential Novel Therapy Targets in Neuroendocrine Carcinomas of the Breast

Bispecific Antibodies and Antibody–Drug Conjugates for Cancer Therapy: Technological Considerations

Personalized treatment in metastatic triple‐negative breast cancer: The outlook in 2020

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