N Engl J Med1
Triple-negative breast cancer
Breast cancer is not a single disease, but rather a global term encompassing a variety of cancers that originate in the breast area. It can be subdivided into three main types depending on what receptors are present or absent on cancer cells. Breast cancers that overexpress oestrogen and/or progesterone receptors are known as hormone receptor-positive. Those that overexpress the human epidermal growth factor receptor 2 are known as HER2-positive. Whereas, breast cancers that don’t express oestrogen, progesterone or HER2 receptors are known as triple-negative breast cancers (TNBC).
Patients with metastatic TNBC (mTNBC) have far worse survival outcomes than those with hormone receptor-positive or HER2-positive metastatic breast cancers. This is not just because mTNBC is very aggressive, but because few targeted treatments have been developed against it. While the introduction of immunotherapy agents has improved clinical outcomes in first-line mTNBC, patients that progress beyond this are limited to single-agent chemotherapy, which is associated with low response rates and poor survival odds.
Approximately 90% of TNBC tumours overexpress trophoblast antigen 2 (Trop-2) – a transmembrane protein that facilitates cancer growth, spread and survival – making it an attractive therapeutic target. Sacituzumab govitecan (TRODELVY®) is a novel antibody-drug conjugate (ADC) that specifically targets cancer cells expressing Trop-2, making it an exciting therapy against this devastating cancer.
ADCs are highly sophisticated drugs consisting of a monoclonal antibody and a cytotoxic payload (chemotherapy), which are attached via a chemical linker. In the case of sacituzumab govitecan, the cytotoxic payload is a topoisomerase I inhibitor called SN-38. What makes ADCs so special is that they combine the useful attributes of both monoclonal antibodies and chemotherapeutic agents in one single drug. In essence, the monoclonal antibody acts as a precise transport vehicle that delivers a highly powerful weapon (chemotherapy) to destroy target cells.
When sacituzumab govitecan is administered to patients, the monoclonal antibody directly seeks out tumour cells expressing Trop-2, while avoiding healthy cells not expressing this antigen. Once the monoclonal antibody component of sacituzumab govitecan binds to a cell expressing Trop-2, the toxic chemotherapy (SN-38) carried by the antibody gets released and internalised into the tumour cell, damaging its DNA and causing apoptosis (Figure 1).
Figure 1. Mechanism of action of sacituzumab govitecan. The ADC first finds and attaches to tumour cells expressing Trop-2. The tumour cell then swallows the ADC. Inside the cell, the chemical linker breaks apart and releases the potent chemotherapy load, resulting in cell death.
The ASCENT study
ASCENT was a phase 3, randomised, open-label trial that compared the efficacy and safety of sacituzumab govitecan vs single-agent chemotherapy (capecitabine, eribulin, gemcitabine or vinorelbine) in patients with mTNBC who had progressed on two prior chemotherapy regimens, one of which must have been in the metastatic setting.
Patients with stable brain metastases that had been treated (with surgery or radiotherapy) at least 4 weeks before starting the study were allowed to participate. In total, 529 patients were enrolled in the study, with 267 patients treated with sacituzumab govitecan and 262 patients treated with chemotherapy. Most patients had no brain metastases at baseline (468 patients without brain metastases vs 61 patients with brain metastases).
The primary endpoint was progression-free survival (PFS) in patients without brain metastases at baseline. This endpoint was strategically chosen to evaluate the efficacy of sacituzumab govitecan in mTNBC without the confounding effect of brain metastases, which are associated with a very poor prognosis. Secondary endpoints included overall survival (OS) and PFS in the full population (patients with and without brain metastases), OS in patients without brain metastases at baseline, objective response rate and safety.
Efficacy in patients without brain metastases
Median PFS was nearly tripled with sacituzumab govitecan vs single-agent chemotherapy (5.6 months vs 1.7 months; p<0.001). Similarly, median OS was significantly extended with sacituzumab govitecan vs single-agent chemotherapy (12.1 months vs 6.7 months; p<0.001). In addition, the percentage of patients who achieved an objective response was 35% with sacituzumab govitecan vs only 5% for single-agent chemotherapy.
Efficacy in the full patient population
In the full patient population, median PFS and OS were also substantially longer with sacituzumab govitecan vs single-agent chemotherapy (PFS: 4.8 months vs 1.7 months; OS: 11.8 months vs 6.9 months).
Efficacy in patients with brain metastases
Exploratory analysis in the small subset of patients with stable brain metastases at baseline showed that the efficacy of sacituzumab govitecan was drastically lower compared with that shown in patients without brain metastases.
In this patient population, median PFS with sacituzumab govitecan was 2.8 months vs 1.6 months with single-agent chemotherapy. Whereas median OS was numerically lower with sacituzumab govitecan vs single-agent chemotherapy (6.8 months vs 7.5 months).
It is important to note that these findings are exploratory, meaning that conclusions should not be made as the data were not statistically powered. Nevertheless, it is interesting that the efficacy of single-agent chemotherapy was almost unchanged regardless of the presence or absence of brain metastases at baseline, while the efficacy of sacituzumab govitecan was drastically better in patients without brain metastases.
The most common treatment-related adverse events of any grade with sacituzumab govitecan were neutropenia (63% vs 43% with chemotherapy), diarrhoea (59% vs 12%), nausea (57% vs 26%), alopecia (46% vs 16%) and fatigue (45% vs 30%).
Meanwhile, the most common treatment-related adverse events of grade 3 or higher with sacituzumab govitecan were neutropenia (51% vs 33% with chemotherapy), leukopenia (10% vs 5%) and diarrhoea (10% vs <1%).
Despite a higher incidence of adverse events in the sacituzumab govitecan arm, the discontinuation rate due to adverse events was 5% in both treatment groups. This is generally regarded as a low discontinuation rate in the context of metastatic cancer, meaning that most patients were able to tolerate and continue with their treatment.
A big stride forward
The ASCENT study demonstrated that sacituzumab govitecan was significantly superior to single-agent chemotherapy for the treatment of mTNBC, with patients experiencing slower disease progression and living substantially longer.
The efficacy benefits with sacituzumab govitecan were so clear in ASCENT that its higher toxicity profile is not regarded as a barrier for use in patients with this terrible type of breast cancer. In fact, sacituzumab govitecan received EU approval in 2021 and is now recommended by the ESMO guidelines as the standard of care for second-line mTNBC, having replaced single-agent chemotherapy.
Overall, the magnitude of these benefits can be considered as a breakthrough in mTNBC, showing that important molecular discoveries followed by the design of highly potent and targeted agents can lead the way forward to improving survival and slowing disease progression in individuals affected by this devastating cancer.
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