Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer

Bardia, Aditya; Mayer, Ingrid A.; Vahdat, Linda T.; Tolaney, Sara M.; Isakoff, Steven J.; Diamond, Jennifer R.; O’Shaughnessy, Joyce; Moroose, Rebecca; Santin, Alessandro D.; Abramson, Vandana G.; Shah, Nikita; Rugo, Hope S.; Goldenberg, David M.; Sweidan, Ala M; Iannone, Robert; Washkowitz, Sarah A.; Sharkey, Robert M.; Wegener, William A.; Kalinsky, Kevin

doi:10.1056/nejmoa1814213

Cited by 617 publications

(598 citation statements)

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“…Consistent with our preclinical in vitro and in vivo results in biologically aggressive endometrial cancer, results from a phase I/II clinical study reported acceptable toxicity and encouraging therapeutic activity of SG against multiple recurrent human epithelial cancers including urothelial cancers and lung cancers (Bardia et al, 2019;Faltas et al, 2016;Gray et al, 2017;Heist et al, 2017;Starodub et al, 2015). Moreover, our group has recently reported an impressive clinical response to SG in a 74-year-old woman with recurrent/chemotherapy-resistant endometrial serous tumor overexpressing Trop-2 (66% reduction of target lesions by RECIST 1.1 criteria for over 10 months of followup) (Han et al, 2018).…”

Section: Discussionsupporting

confidence: 83%

“…Furthermore, other encouraging results of treatment with SG were previously described in a cohort of 108 heavily pretreated metastatic triple‐negative breast cancers. These patients had an objective response rate of 33.3%, median response duration of 7.7 months, and a clinical benefit rate of 45.4% (Bardia et al , ). As a result of these encouraging clinical findings in breast cancer patients, SG has received breakthrough therapy designation from the FDA for the treatment of TNBC patients with metastatic disease who have failed at least two prior therapies.…”

Section: Discussionmentioning

confidence: 99%

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Sacituzumab govitecan, an antibody‐drug conjugate targeting trophoblast cell‐surface antigen 2, shows cytotoxic activity against poorly differentiated endometrial adenocarcinomas in vitro and in vivo

et al. 2020

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Endometrial cancer is the most common gynecologic malignancy in developed countries. The antibody–drug conjugate (ADC) sacituzumab govitecan (SG) targets trophoblast cell‐surface antigen‐2 (Trop‐2) – a cell‐surface glycoprotein highly expressed in many epithelial tumors – and delivers the active metabolite of irinotecan SN‐38 to Trop‐2‐positive tumor cells. We evaluated Trop‐2 expression in endometrial endometrioid carcinoma (EC) tissues and the activity of SG against primary poorly differentiated EC cell lines and xenografts. Trop‐2 expression was assessed in 143 formalin‐fixed–paraffin‐embedded tumors and seven primary tumor cell lines by immunohistochemistry and flow cytometry, respectively. Cell viability of primary tumor cell lines was assessed following exposure to SG, or control antibodies. Antibody‐dependent cell cytotoxicity (ADCC) against Trop‐2‐positive and Trop‐2‐negative EC cell lines was measured in vitro using 4‐h chromium release assays. A Trop‐2‐positive EC xenograft model was used to determine the in vivo activity of SG. Moderate‐to‐strong staining was detected in 84% (120/143) of EC samples, whereas 43% (3/7) of the primary EC cell lines tested overexpressed Trop‐2. EC cell lines overexpressing Trop‐2 were significantly more sensitive to SG compared to control ADC (P = 0.014 and P = 0.005). Both SG and the unconjugated parental antibody hRS7 mediated high ADCC against Trop‐2‐positive cell lines. Moreover, SG induced significant bystander killing of Trop‐2‐negative tumors cocultured with Trop‐2‐positive tumors. In the xenograft model, intravenous administration of SG twice weekly for three weeks was well tolerated and demonstrated impressive tumor growth inhibition against poorly differentiated, chemotherapy‐resistant EC xenografts (P = 0.011). In summary, SG is a novel ADC with remarkable preclinical activity against poorly differentiated EC cell lines overexpressing Trop‐2. These findings warrant future clinical trials.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Sacituzumab govitecan, an antibody‐drug conjugate targeting trophoblast cell‐surface antigen 2, shows cytotoxic activity against poorly differentiated endometrial adenocarcinomas in vitro and in vivo

et al. 2020

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“…GUSi's effects on irinotecan's GI damage and antineoplastic efficacy were tested in vivo using a preclinical model of inflammatory breast cancer. Irinotecan formulations have been examined in mouse models of breast cancer (24), and human clinical trials for breast cancer have used SN38 combination therapies (25). Furthermore, breast cancer models were chosen to avoid confounding effects of microbial dysbiosis caused by the inflammatory tumor microenvironment of colorectal cancer (26,27).…”

Section: Gus Inhibition Alleviates Irinotecan-induced Gut Toxicity Inmentioning

confidence: 99%

Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy

Bhatt

Pellock

Biernat

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

142

104

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Irinotecan treats a range of solid tumors, but its effectiveness is severely limited by gastrointestinal (GI) tract toxicity caused by gut bacterial β-glucuronidase (GUS) enzymes. Targeted bacterial GUS inhibitors have been shown to partially alleviate irinotecan-induced GI tract damage and resultant diarrhea in mice. Here, we unravel the mechanistic basis for GI protection by gut microbial GUS inhibitors using in vivo models. We use in vitro, in fimo, and in vivo models to determine whether GUS inhibition alters the anticancer efficacy of irinotecan. We demonstrate that a single dose of irinotecan increases GI bacterial GUS activity in 1 d and reduces intestinal epithelial cell proliferation in 5 d, both blocked by a single dose of a GUS inhibitor. In a tumor xenograft model, GUS inhibition prevents intestinal toxicity and maintains the antitumor efficacy of irinotecan. Remarkably, GUS inhibitor also effectively blocks the striking irinotecan-induced bloom of Enterobacteriaceae in immunedeficient mice. In a genetically engineered mouse model of cancer, GUS inhibition alleviates gut damage, improves survival, and does not alter gut microbial composition; however, by allowing dose intensification, it dramatically improves irinotecan's effectiveness, reducing tumors to a fraction of that achieved by irinotecan alone, while simultaneously promoting epithelial regeneration. These results indicate that targeted gut microbial enzyme inhibitors can improve cancer chemotherapeutic outcomes by protecting the gut epithelium from microbial dysbiosis and proliferative crypt damage. microbiome | chemotherapy | cancer | gastrointestinal toxicity I rinotecan (CPT-11) is essential for treating colorectal and pancreatic cancers and is frequently administered as a mixture with 5-fluorouracil and/or oxaliplatin. Ongoing clinical trials seek to extend irinotecan to other forms of cancer. However, irinotecan causes both myelosuppression and gastrointestinal (GI) side effects, including mucositis and late-onset diarrhea, which are often dose limiting: 88% of irinotecan patients develop diarrhea, with 30% experiencing acute grade 3 to 4 diarrhea (1-3). This toxicity is frequently refractory to antimotility drugs. Thus, treating irinotecaninduced diarrhea is a significant clinical need (4, 5).The irinotecan prodrug is activated in vivo to SN38, a potent topoisomerase I inhibitor (6) that retards the growth of rapidly proliferating cells in tumors and the intestinal epithelium, which renews every 5 d. SN38 is detoxified through the addition of glucuronic acid (GlcA) to form SN38-G, a compound marked for elimination via the GI tract. Gut commensal bacterial β-glucuronidase (GUS) proteins remove GlcA from SN38-G. Reactivated SN38 inflicts epithelial damage, resulting in bleeding diarrhea and acute weight loss in animal models (7). We reduced irinotecan-induced gut toxicity using inhibitors that selectively, nonlethally, and potently block the actions of gut bacterial GUS enzymes (8,9). The utility of GUS inhibition also extends to drugs be...

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“…This necessitated expansion of the same study, while restricting additional enrollment, to include less pretreated patients. In the subsequent expanded report on 108 patients, treatment with SG was associated with an ORR of 33.3%, among patients who had received at least two previous therapies for their mTNBC (median, three). The median duration of response was 7.7 months, while the mPFS was 5.5 months, and the mOS was 13.0 months.…”

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-hziy in Refractory Metastatic Triple-Negative Breast Cancer

Cited by 617 publications

References 33 publications

Sacituzumab govitecan, an antibody‐drug conjugate targeting trophoblast cell‐surface antigen 2, shows cytotoxic activity against poorly differentiated endometrial adenocarcinomas in vitro and in vivo

Sacituzumab govitecan, an antibody‐drug conjugate targeting trophoblast cell‐surface antigen 2, shows cytotoxic activity against poorly differentiated endometrial adenocarcinomas in vitro and in vivo

Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy

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

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