Sacituzumab Govitecan Sets the Stage for Substratification of TNBC

Although PD-L1 positivity has become a biomarker of response to immunotherapy in metastatic triple-negative breast cancer (TNBC), the target antigens for antibody-drug conjugates (ADCs) are the markers that have the greatest potential to change the way TNBC is classified and treated, according to Aditya Bardia, MD, MPH.

Currently, sacituzumab govitecan-hziy (Trodelvy), a Trop-2–directed ADC, is the only ADC that is approved for the treatment of patients with metastatic TNBC. The agent received accelerated approval in April 2020 for patients with metastatic TNBC who have received at least 2 prior therapies. 

“Besides sacituzumab govitecan, there’s another ADC that targets Trop-2 called DS-1062, or datopotamab deruxtecan. There’s also an ADC that targets HER3, which is pretty exciting as well. [All of] the different ADCs targeting different antigens will change the way we classify TNBC,” said Bardia. 

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on breast cancer, Bardia, director of Precision Medicine at the Center for Breast Cancer and founding director of the Molecular and Precision Medicine Metastatic Breast Cancer Clinic, Massachusetts General Hospital Cancer Center, and assistant professor of medicine, Harvard Medical School, discussed the integration of ADCs and immunotherapy into the treatment landscape in metastatic TNBC and the future of AKT inhibitors in the field. 

OncLive^®: What about the mechanism of action of sacituzumab govitecan makes it an ideal treatment in TNBC? 

Bardia: Sacituzumab govitecan is a Trop-2–directed ADC. The antibody targets Trop-2, which is overexpressed in TNBC. It has a hydrolysable linker and an SN-38 toxic payload. The idea is that the ADC would find the Trop-2–positive cancer cells and release SN-38 to the cancer cells. The drug also has a bystander effect because of the hydrolysable linker, so it can deliver SN-38 into the tumor microenvironment, which can also affect cells that do not express Trop-2. 

What data support the use of sacituzumab govitecan as a third-line standard in metastatic TNBC?

The phase 3 ASCENT trial compared sacituzumab govitecan with physician’s choice of chemotherapy as third-line and beyond therapy for patients with metastatic TNBC. The results showed an improvement in progression-free survival [PFS] and overall survival [OS] with sacituzumab govitecan, so it should be considered as an option for patients with metastatic TNBC in the third- or later-line setting.

Is this agent under study in other breast cancer subtypes?

This agent is being explored in other settings, including estrogen receptor [ER]–positive metastatic breast cancer, because even ER-positive breast cancer expresses Trop-2. The TROPICS-02 trial [NCT03901339] is evaluating this drug as a third-line or later therapeutic option for patients with metastatic ER-positive breast cancer. In addition, this agent is being combined with other targeted agents, PARP inhibitors, and immunotherapy for patients with metastatic disease. The ongoing NeoSTAR trial [NCT04230109] is looking at sacituzumab govitecan as a neoadjuvant therapy for patients with localized TNBC.

How have the data from IMpassion130, IMpassion131, and KEYNOTE-355 affected the landscape?

IMpassion130 was the first phase 3 trial [that demonstrated a benefit] with immunotherapy for patients with metastatic TNBC. Data from that trial led to the approval of atezolizumab [Tecentriq]. The trial looked at nab-paclitaxel [Abraxane] plus atezolizumab vs nab-paclitaxel alone and showed an improvement in PFS and OS [with atezolizumab] in patients with PD-L1–positive metastatic TNBC. 

IMpassion131 was essentially the same trial, but instead of nab-paclitaxel, looked at paclitaxel, and somewhat surprisingly, did not show an improvement in PFS and OS [with atezolizumab]. This led the FDA to issue a warning that if you’re using atezolizumab, use nab-paclitaxel not paclitaxel as the chemotherapy backbone.

KEYNOTE-355 evaluated different chemotherapy backbones––platinum, nab-paclitaxel, and paclitaxel––in combination with pembrolizumab [Keytruda] and showed an improvement in PFS compared with the [chemotherapy alone group] in PD-L1–positive, metastatic TNBC. The way PD-L1 was assessed in KEYNOTE-355 was based on the CPS [combined positive score], and a CPS score of 10 or greater was associated with improvement in PFS. The findings from KEYNOTE-355 led to the approval of pembrolizumab in that setting.

When it comes to immunotherapy, how do you choose between the 2 agents that are available?

At this time, we have 2 immunotherapy agents that are FDA approved: atezolizumab and pembrolizumab. Essentially, it’s up to the physician to choose either of those immunotherapy agents. If one were to choose atezolizumab, the chemotherapy backbone of choice is nab-paclitaxel, because that is what was studied in the IMpassion130 trial. 

With pembrolizumab, you have the option of using other chemotherapy agents as well, such as platinum. You can also use nab-paclitaxel or paclitaxel. The KEYNOTE-355 trial demonstrated that the combination of any of these chemotherapy backbones plus pembrolizumab resulted in superior PFS compared with chemotherapy alone for PD-L1–positive metastatic TNBC.

How does PD-L1 testing differ for atezolizumab and pembrolizumab?

The approval of pembrolizumab and atezolizumab is for PD-L1–positive metastatic TNBC, although the type of assay is different. With pembrolizumab, [you have to evaluate a patient’s] CPS score, which looks at the expression of PD-L1 in the tumor cells as well as in the tumor microenvironment. On the other hand, with atezolizumab, the Ventana SP142 assay should be used, which looks at PD-L1 expression in the immune microenvironment. They’re different assays, and the cutoffs are also different. It’s 1% or higher for the use of atezolizumab, and for pembrolizumab, it’s a CPS score with a cutoff of 10 or higher.

Do you anticipate that AKT inhibitors could play a role in TNBC, despite the data we saw from the IPATunity trial? 

AKT inhibitors are being evaluated for patients with metastatic TNBC, in particular, those tumors that harbor an activation of the PI3K/AKT pathway. LOTUS was a randomized phase 2 trial, which demonstrated that a taxane plus ipatasertib was associated with an improvement in PFS compared with a taxane alone. 

These data led to the registrational phase 3 IPATunity130 trial, which was negative. It did not show any improvement in PFS with ipatasertib plus a taxane vs a taxane alone. Even in the PI3KCA-altered subgroup, there was no improvement in PFS [with the combination], so this is a bit disappointing that we don’t have this targeted therapy for patients with metastatic disease, but we await additional data—specifically, the OS as well as biomarker analysis, so we can understand this better.