Tackling metastatic triple-negative breast cancer with sacituzumab govitecan

ABSTRACT

Introduction Metastatic triple-negative breast cancer (TNBC) is an aggressive cancer with poor survival that is difficult to treat due to a lack of targeted options. Conventional therapies targeting hormone receptors (HR) and human epidermal growth factor 2 (HER2) are ineffective and often chemotherapy is standard-of-care. Sacituzumab govitecan is an antibody drug conjugate (ADC) comprised of an active metabolite of irinotecan, SN-38, bound to a humanized monoclonal antibody targeting trophoblastic cell-surface antigen 2 (Trop-2). Trop-2 is highly expressed on the surface of TNBC cells, making it an attractive target. Areas covered We explore the mechanism, pharmacology, efficacy, safety, and tolerability of sacituzumab govitecan. A literature search was conducted via PubMed using keywords such as ‘sacituzumab govitecan,’ and ‘metastatic TNBC.’ Expert opinion Sacituzumab govitecan has promising survival benefits in patients with previously treated mTNBC based on data from the ASCENT trial. Common adverse effects were neutropenia, diarrhea, and nausea, however these effects were manageable with supportive care. Sacituzumab govitecan has shown promise in cancers outside of TNBC, such as urothelial and lung and is being evaluated in HR-positive breast cancers. It is likely we will see this therapy used in combination with other novel targeted agents as current clinical trials mature.

KEYWORDS:

• Sacituzumab govitecan
• IMMU-132
• trophoblastic cell surface antigen 2 (Trop-2)
• triple-negative breast cancer (TNBC)
• antibody drug conjugate (ADC)
• SN-38

Article highlights

• Triple-negative breast cancer (TNBC) is a sub-type of breast cancer which lacks the estrogen receptor (ER), progesterone receptor (PR), and overexpression of the human epidermal growth factor 2 (HER2). Given lack of targets, TNBC is difficult to treat and overall survival (OS) remains poor.

• Targeted therapies are now available for patients with metastatic TNBC (mTNBC) with expression of programmed death-ligand 1 (PD-L1) and BRCA mutations. However, the majority of patients with mTNBC are PD-L1-negative and/or BRCA wildtype. Resistance is also common with these new targeted therapies.

• Sacituzumab govitecan is an antibody drug conjugate (ADC) which targets trophoblastic cell surface antigen 2 (Trop-2). Sacituzumab govitecan is comprised of SN-38, an active metabolite of irinotecan, a hydrolysable linker, and a humanized monoclonal antibody.

• Trop-2 is highly expressed on the surface of TNBC cells. As such, sacituzumab govitecan was widely studied in mTNBC.

• The Phase I/II clinical trial evaluating the use of sacituzumab govitecan in patients with previously treated advanced epithelial cancers, demonstrated benefit in OS and progression free survival (PFS) in patients with mTNBC when compared to historical controls. These positive outcomes led to the accelerated approval for the use of sacituzumab govitecan in pre-treated mTNBC by the Food and Drug Administration (FDA).

• The Phase III ASCENT trial confirmed the benefit of sacituzumab govitecan, in patients without brain metastasis, after at least two prior treatments, one which could be in the neoadjuvant or adjuvant setting with a superior OS and PFS when compared to physician’s choice standard-of-care chemotherapies. The results of this trial led to regular approval by the FDA.

• Sacituzumab govitecan is FDA approved for patients with locally advanced or mTNBC who have received two or more prior therapies with at least one in the metastatic setting.

• The most common adverse events observed with sacituzumab govitecan were neutropenia, diarrhea, and nausea. Many patients had adverse events but most improved with supportive care.

• Sacituzumab govitecan has become standard-of-care for patients with mTNBC who have received prior chemotherapy.

• Sacituzumab govitecan has shown encouraging results in hormone receptor positive breast cancers and across other epithelial cancers. In addition, clinical trials are underway to evaluate sacituzumab govitecan in combination with immunotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors.

Declaration of interest

The author(s) have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Information resources

For further reading, please visit clinicaltrial.gov to read more about current clinical trials investigating sacituzumab govitecan. In addition, visit PubMed and search TROPiCS-02 to read about an on-going clinical trial evaluating sacituzumab govitecan in HR-positive/HER2-negative metastatic breast cancer.

Additional information

Funding

The author(s) have no funding to report.