On April 22, 2020, the FDA approved sacituzumab govitecan for the treatment of some patients with a particularly aggressive form of breast cancer named metastatic triple-negative breast cancer. It is used in adult patients who have received at least two previous therapies. It is the first ADC (antibody-drug conjugate) drug approved by the FDA specifically for relapsed or refractory metastatic triple-negative breast cancer. It is also the first FDA-approved anti–Trop-2 antibody-drug conjugate.
Chemotherapy has always been the main treatment for metastatic triple-negative breast cancer which is an aggressive breast cancer with limited treatment options. Sacituzumab govitecan’s approval represents a new targeted therapy for patients with this aggressive malignancy.
Antibody-drug conjugates or ADCs are highly targeted biopharmaceutical drugs that combine monoclonal antibodies specific to surface antigens present on specific tumor cells with highly potent anti-cancer agents linked by chemical linkers. With ten approved drugs on the market, ADCs have become a powerful class of therapeutic agents in oncology and hematology.
Mechanism of Action
Sacituzumab govitecan, brand name Trodelvy, previously known as IMMU-132. It consists of sacituzumab and SN-38 with a linker in between. Sacituzumab is a kind of molecule named a monoclonal antibody, it targets the Trop-2 protein and attaches to it. The Trop-2 protein is found in over 90% of triple-negative breast cancers. SN-38 is a topoisomerase I inhibitor chemotherapy. It is an inhibitor carried by sacituzumab that targets the specific area, making it more effective in treating cancer cells and less toxic to healthy cells.
By conjugating a higher number of SN-38 molecules to the antibody (drug-to-antibody ratio = 7-8:1), with higher doses (10 mg per kg of body weight) and repeated treatment cycles (Days 1 and 8 of 21-day cycles), it is possible to achieve enhanced, targeted, drug uptake.
On binding to Trop-2, the hRS7 antibody, both in free and conjugated form, is internalized and delivers SN-38 into the tumor cell. Following internalization, SN-38 is released both intracellularly as well as 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.
In brief, Sacituzumab govitecan was designed to deliver SN-38 chemotherapy to cancer cells in a targeted way by attaching SN-38 to the sacituzumab. Then, sacituzumab carries SN-38 into triple-negative cancer cells. In this way, SN-38 is less toxic to healthy cells and it is more effective in treating cancer cells.
There are some side effects for sacituzumab govitecan. The most common side effects which reported before (occurring in 25% or more of patients) were 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% of patients) were neutropenia, white blood cell count decreased, anemia, hypophosphatemia, diarrhea, fatigue, nausea, and vomiting.
There were 2% 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.
1. Phase I/II Study of IMMU-132 in Patients With Epithelial Cancers – NCT01631552
2. ASCENT-Study of Sacituzumab Govitecan in Refractory/Relapsed Triple-Negative Breast Cancer (ASCENT) – NCT02574455
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Sacituzumab Govitecan Approved in Metastatic Triple-negative Breast Cancer
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