The U.S. Food and Drug Administration (FDA) has approved sacituzumab govitecan* (Trodelvy™; Immunomedics) for the treatment of adult patients with metastatic triple-negative breast cancer (mTNBC) who have received at least two prior therapies for patients with relapsed or refractory metastatic disease.
Sacituzumab govitecan, previously known as IMMU-132, is Immunomedics’ lead product and the most advanced program in the company’s unique antibody-drug conjugate (ADC) platform. The drug binds the humanized antitrophoblast cell-surface antigen 2 (Trop-2) monoclonal antibody (mAb) hRS7 IgG1κ through the cleavable CL2A linker to the anti-cancer drug SN-38 to kill cancer cells. Trop-2 is expressed in more than 85% of all cancers, including breast cancer and TNBC.
SN-38 is the active metabolite of irinotecan, a drug that has revolutionized the applicability of camptothecins as predominant topoisomerase I inhibitor for anti-cancer therapy.
On binding to Trop-2, hRS7, both in free and conjugated form, is internalized and delivers SN-38 into the tumor cell. Following internalization, SN-38 is released in both intracellularly and in the tumor microenvironment, thereby delivering therapeutic concentrations of the active drug in bystander cells to which the conjugate has not bound. After the intracellular uptake of SN-38, both sacituzumab-bound tumor cells and adjacent tumor cells are killed by the extracellular release of the active drug. 
With the FDA’s decision, sacituzumab govitecan is the eight approved and available ADCs reaching the market, making these targeted drugs a powerful class of therapeutic agents in oncology and hematology.
Trop-2 is an attractive target and may help address multiple types of cancer.  Hence, sacituzumab govitecan is currently being evaluated as a treatment for eight hard-to-treat solid cancers.
An aggressive cancer
Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer, accounting for up to 20% of all breast cancers.  TNBC is diagnosed more frequently in younger and premenopausal women and is highly prevalent in African American and Hispanic women.
TNBC cells lack estrogen or progesterone hormone receptors, or very much of the human epidermal growth factor receptor 2 (HER2) – hence the term triple-negative. This means that medicines that target these receptors are not typically effective in TNBC. While standard chemotherapy may be available to treat TNBC, there is currently no approved standard of care for people with previously-treated advanced or metastatic TNBC. 
Using Immunomedics’ proprietary drug developing platform, sacituzumab govitecan is the first antibody-drug conjugate (ADC) that targets the Trop-2 antigen, a cell-surface protein highly expressed by approximately 90% of TNBC tumors. 
The drug’s mechanism of action involves binding to the Trop-2 antigen, which is highly expressed in many epithelial cancers including TNBC and releases the cytotoxic SN-38 inside the tumor cell and the tumor microenvironment.
Sacituzumab govitecan was approved based on Phase II study results demonstrating an objective response rate (ORR) of 33.3% and a median duration of response of 7.7 months. The drug also delayed tumor progression or death by more than 5.5 months, and, according to study results published in the New England Journal of Medicine, helped this group of heavily pretreated patients live 13 months.
The Phase III ASCENT trial provides additional data for sacituzumab govitecan for the treatment of metastatic TNBC.
Immunomedics recently announced that the Phase III confirmatory ASCENT study (NCT02574455) of [sacituzumab govitecan] in metastatic TNBC, with over 500 patients enrolled, will be stopped early due to compelling efficacy across multiple endpoints, based on the unanimous recommendation of the independent Data Safety Monitoring Committee (DSMC). Topline results will be presented later this year.
Breakthrough Therapy and Priority Review
Sacituzumab govitecan, which was granted Breakthrough Therapy Designation and Priority Review, was approved under the FDA’s Accelerated Approval Program based on the objective response rate (ORR) and duration of response (DoR) observed in a single-arm, multicenter Phase II study. Continued approval may be contingent upon verification of clinical benefit in the confirmatory Phase III ASCENT study, which was recently stopped by the independent Data Safety Monitoring Committee (DSMC) for compelling evidence of efficacy across multiple endpoints.
“The approval of [sacituzumab govitecan], the first ADC approved specifically for metastatic TNBC, an aggressive cancer with a poor prognosis and few effective therapies, will give clinicians a novel tool for treating patients with this disease,” noted Aditya Bardia, MD, MPH, Director of Precision Medicine at the Center for Breast Cancer, Massachusetts General Hospital Cancer Center and Assistant Professor of Medicine at Harvard Medical School.
Bardia was the lead investigator of the Phase II study.
“In our trial, [sacituzumab govitecan] demonstrated clinically meaningful responses in patients with difficult-to-treat metastatic TNBC and moves the needle towards better outcomes for patients with metastatic breast cancer.”
In the single-arm Phase II study, [sacituzumab govitecan] demonstrated an ORR of 33.3 percent (95% CI: 24.6, 43.1) and a median DoR of 7.7 months (95% CI: 4.9, 10.8), as determined by local assessment, in 108 adult TNBC patients who had previously received a median of three prior systemic therapies in the metastatic setting (range: 2-10). As part of their treatment, these patients received sacituzumab govitecan at a dose level of 10 mg per kilogram of body weight. 
“We are proud to bring [sacituzumab govitecan] to patients with metastatic TNBC who are in dire need of new options. Trodelvy has the potential to become a standard of care in the management of TNBC, and we anxiously await the results of ongoing studies in other types of metastatic breast cancer,” noted Loretta M. Itri, Chief Medical Officer of Immunomedics.
“This approval highlights the potential of our unique ADC platform and strengthens the premise that the Trop-2 antigen found in many solid cancers is an important target for drug delivery. We are committed to broadening the potential use of [sacituzumab govitecan] in other Trop-2-expressing cancers, especially those with unmet need.”
Black box warning
Sacituzumab govitecan carries a black box warning for severe neutropenia and severe diarrhea. The most common adverse reactions occurring in 25 or more percent of patients included nausea, neutropenia, diarrhea, fatigue, anemia, vomiting, alopecia, constipation, decreased appetite, rash, and abdominal pain. The most common Grade 3 or 4 adverse events occurring in more than 5 percent of patients were neutropenia, white blood cell count decreased, anemia, hypophosphatemia, diarrhea, fatigue, nausea, and vomiting. Two percent of patients discontinued treatment due to adverse events. There were no deaths related to treatment and no severe cases of neuropathy or interstitial lung disease.
“[Sacituzumab govitecan]’s approval is a major milestone in our transformation from a research-based organization to a fully-integrated biopharmaceutical company, underscoring our commitment to bring innovative therapies to patients with hard-to-treat cancers,” observed Behzad Aghazadeh, Executive Chairman of Immunomedics.
“We are grateful to all of the patients, their families, physicians, and nurses who participated in our clinical trials and played a significant role in making this moment possible.”
* Sacituzumab govitecan-hziy in the United States
Phase I/II Study of IMMU-132 in Patients With Epithelial Cancers – NCT01631552
ASCENT-Study of Sacituzumab Govitecan in Refractory/Relapsed Triple-Negative Breast Cancer (ASCENT) – NCT02574455
 TRODELVY™ Prescribing Information. Morris Plains, NJ: Immunomedics Inc, 2020.
 Starodub AN, Ocean AJ, Shah MA, et al. First-in-human trial of a novel anti-Trop-2 antibody-SN-38 conjugate, sacituzumab govitecan, for the treatment of diverse metastatic solid tumors. Clin Cancer Res 2015;21: 3870-3878.
 Sharkey RM, McBride WJ, Cardillo TM, et al. Enhanced delivery of SN-38 to human tumor xenografts with an anti-Trop-2-SN-38 antibody conjugate (sacituzumab govitecan). Clin Cancer Res 2015;21:5131-5138.
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 Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer. N Engl J Med. 2019;380(8):741–751. doi:10.1056/NEJMoa1814213