Immunotherapy-Based Endeavors Could Alter Treatment Landscape in Metastatic TNBC

Yuan Yuan, MD, PhD

Triple-negative breast cancer (TNBC) remains a difficult-to-treat subtype within the breast cancer population. However, immunotherapy-based approaches could eventually help improve outcomes and long-term prognosis for these patients, according to Yuan Yuan, MD, PhD.

Yuan, director of Breast Oncology at Cedars-Sinai Cancer, added that finding ways to increase the T cell counts in TNBC tumors to make them “immune hot” and open a new realm of treatment options. “Eventually, I would hope every other disease type will mimic our success in HER2-positive [breast cancer], where we are able to see a lot of long-term survivors without active disease. That's our goal,” she said.

In an interview with OncLive^®, Yuan discussed the role immune checkpoint inhibitors have played in the treatment of TNBC, ongoing efforts to investigate the role of immunotherapy within TNBC and other subtypes of breast cancer, and the work Cedars-Sinai is conducting to spread awareness for patient screening and care.

OncLive^®: How have immune checkpoint inhibitors affected the treatment paradigm in TNBC?

Yuan: [In 2019], we had an FDA approval for atezolizumab [Tecentriq] in combination with nab-paclitaxel [Abraxane], specifically as a frontline, metastatic treatment in PD-L1–positive TNBC. Initial data had shown that comparison with chemotherapy alone, the combination of atezolizumab plus chemotherapy had a significant progression-free survival [PFS] benefit, However, Genentech ran the phase 3 [IMpassion131] trial [NCT3125902], using atezolizumab, but combined with paclitaxel, as a frontline therapy. IMpassion131 turned out to be negative, with the PFS curves overlapping with no benefit at all. Due to these results, [the indication] for atezolizumab plus chemotherapy was withdrawn [for TNBC in 2021].

We also had the [phase 3] KEYNOTE-355 trial [NCT02819518], which was a somewhat similar design [to IMpassion131], but it used a different immune checkpoint inhibitor, pembrolizumab [Keytruda], in combination with physician’s choice of chemotherapy, including nab-paclitaxel, paclitaxel, or the combination of gemcitabine and carboplatin. The 3 chemotherapy regimens were used with or without pembrolizumab, and by adding pembrolizumab, PFS improved by 4.1 months, and there was also an overall survival [OS] benefit. That led to overwhelming FDA approval of [pembrolizumab plus chemotherapy in locally recurrent unresectable or metastatic TNBC].

Pembrolizumab data were also translated in the neoadjuvant space in the [phase 3] KEYNOTE-522 trial [NCT03036488], examining the backbone of carboplatin and paclitaxel followed by doxorubicin and cyclophosphamide and adding pembrolizumab. We were able to improve pathological complete response [pCR]. [The addition of pembrolizumab] translated to better projected outcome, including a 3-year event-free survival benefit. Pembrolizumab is the only solo immune checkpoint inhibitor approved in early-stage breast cancer.

Are there other areas of interest for investigating immune checkpoint inhibitors in breast cancer?

At this moment, there is no immune checkpoint inhibitor in HER2-positive tumors, or in estrogen receptor [ER]–positive, HER2-negative disease. There are many ongoing trials looking at adding atezolizumab or pembrolizumab for HER2-positive metastatic disease. The trials are still ongoing.

That is the tip of the iceberg showing the efforts [to investigate immune checkpoint inhibitors] in breast cancer, and [this serves as] proof of principle that immunotherapy does help. A lot of effort beyond this scope is trying to use a combination therapy approach to try to improve the potential probability for those tumors to turn from immune cold to immune hot. You can see a surge of combination trials in the recent years.

If investigators find that immune checkpoint inhibitors have efficacy in breast cancer subtypes beyond TNBC, what could that mean for those treatment spaces?

Conventionally, ER-positive, HER2-negative disease is considered an immune-cold tumor. In the pathology slides, you do not see much immune infiltration. One day, if we can change that, that brings the probability for durable responses [to immune checkpoint inhibitors]. We do not want to use the buzzword “cure,” but one day, maybe that will give us an opportunity to get long-term disease control by leveraging the immune system to do its job and not allowing the disease to progress.

As with any beneficial therapy, there is always a flip side. Immunotherapy can be a double-edged sword. Once you activate the immune system, T cells can wake up and start to attack healthy, normal cells. That triggers a series of potential immune toxicities, such as thyroiditis, hepatitis, and pneumonitis. Among the most common of these is endocrinopathy, where the endocrine organs tends to be attacked. Patients need to be aware, and sometimes these immune toxicities can be late onset. For example, a patient could have finished treatment 18 months ago, then have a late-onset toxicity that would not be expected with a conventional chemotherapy approach. When you stop chemotherapy, the toxicity stops, but these [immunotherapy] toxicities can be late onset.

How has the emergence of HER2-low as a subtype in breast cancer affected treatment decisions? What has it meant for patients with TNBC?

HER2-positive is defined by either immunohistochemistry [IHC] 3+ pass or IHC 2+ with fluorescent in situ hybridization [FISH] amplified. Those low expression levels of IHC 1+ or 2+ were conventionally considered HER2-negative, but now [the phase 3] DESTINY-Breast04 trial [NCT03734029] data showed us such a great separation of the PFS and OS curves [with fam-trastuzumab deruxtecan-nxki (Enhertu) vs chemotherapy in patients with metastatic HER2-low breast cancer]. It was a historical moment.

However, as noted in the trial, it enrolled only a small number [of patients with] TNBC. Despite the small number, you can see in that cohort of patients, the PFS curve is also separating [for trastuzumab deruxtecan vs chemotherapy]. Because this is a huge area of unmet need, the FDA did not specifically differentiate between ER-negative/HER2-low or ER-positive/HER2-low [in its approval of trastuzumab deruxtecan for HER2-low disease].

This is an important distinction because I get asked a lot about how sequence treatments. We officially have 2 antibody-drug conjugates [ADCs] in TNBC, with the sacituzumab govitecan-hziy [Trodelvy] data from the phase 3 ASCENT trial (NCT02574455)] showing PFS and OS benefits [vs chemotherapy]. If I was asked to make choices for sequencing, I would prefer that sacituzumab govitecan goes first, then trastuzumab deruxtecan can come in as the next line, just because of the amount of patient evidence [we have for both agents].

Of course, in the future, there are many trials ongoing right now, including studies looking at datopotamab deruxtecan (DS-1062a), which is a TROP2-targeting [IgG1 monoclonal] antibody, and the payload is deruxtecan. We are looking forward to seeing data there. There are a few other companies also working on other HER2-targeted ADCs, and soon we will be asking the question of how we sequence these ADCs. It will be a good headache to have.

What unmet needs remain in TNBC?

Despite all the excitement we’ve had over immune checkpoint inhibitors, even with the ADCs now, we are improving slightly on our PFS and OS benefits. The OS for metastatic TNBC has always been very challenging. With old data, [median OS] ranged from 12 to 18 months. Now we’re able to slide that to 18 to 24 months for certain populations, but not every patient.

[TNBC] is a very heterogeneous disease, and it can be classified into at least 6 different subtypes, [and subtypes such as] mesenchymal and mesenchymal stem-like are extremely chemotherapy resistant. Basal-like is slightly better with some chemosensitivity, and the immunomodulatory subtype is prone to responding to immunotherapy. However, there is a lot more work that needs to be done for those fast progressors who seem to not respond to anything, which is extremely frustrating. Even in a lot of clinical trials, including KEYNOTE-355, in the eligibility criteria, those fast progressors will not get a chance to enroll. Outside of the [immunomodulatory subtype], we still have a lot more work to be done.

We do next-generation sequencing nowadays as a standard care, but a lot of genomic mutations that we discover don’t have an actionable plan. There are no drugs for [some mutations], which is another big frustration. For example, FGF amplification has been found a lot more often, and this tends to be a very chemotherapy resistant. We know that in the space of urologic cancer, such as bladder cancer, we have FGF inhibitors already FDA approved. But those inhibitors are unlikely to work for our breast cancer. They may work for FGF fusions, but not for the amplifications. This is a calling for the industry. We wanted to do a precision medicine approach [across oncology], but we are not there yet for every single disease type.

To go to PIK3CA mutations, we know that alpelisib [Piqray] was FDA approved to treat ER-positive/HER2-negative disease. However, efficacy in TNBC is difficult to assess because when the drug is combined with chemotherapy, it becomes extremely toxic, hard to tolerate, and the combination does not appear to have a lot of efficacy either. There is still lots of frustration when it comes to TNBC. [A patient with TNBC] can have the same mutation or same alteration [as a patient with a different subtype with breast cancer] yet have a different outcome. We do not understand why.

Is there any ongoing research in TNBC that intrigues you?

The holy grail to leverage immunotherapy better is to turn an immune-cold tumor to immune hot. Adding a combination treatment or novel inhibitors [could be a way to] turn an immune-cold tumor to immune hot.

A trial just came over to Cedars-Sinai using ivermectin. With ivermectin, we need to be cautious because if there has been some bad media throughout the pandemic with people starting to take the horse dose of ivermectin, which can be toxic. However, 5 years back, a group at City of Hope had done great research with a drug screening program and identified ivermectin as being immune potent. It was safely being used for treating parasites all over the world, and over 500,000 people have been treated, if not more than that, so safety is there.

Now, how do we repurpose this antiparasite drug into an anticancer drug? The preclinical work in mice models identified that under immune microscopy, the immune-cold tumor can become a hot tumor after ivermectin treatment. When you add an immune checkpoint inhibitor on top of [ivermectin], you seem to have much better disease control, and some of the tumor would disappear. After that, if you rechallenge by injecting more tumor cells into these mice, those tumor cells do not grow.

We now aim to conduct the first-in-human combination trial of oral ivermectin plus an intravenous immune checkpoint inhibitor. That is going through an institutional review board right now, and we are hoping to activate that. I seem to get emails every week. There are enough people that want [to use ivermectin], but the precaution here is that we are not asking people to just start taking ivermectin. We want to make sure patients come in, enroll, and then are evaluated properly as a part of the study.

Another approach I worked on with a team also at City of Hope looked at an oncolytic virus­, an engineered poxvirus, to study in a combination trial. There are a lot of efforts ongoing.

[At Cedars-Sinai], our radiation oncologist team, including Stephen L. Shiao, MD, PhD, has worked on a combination of radiation therapy plus pembrolizumab and a CSF1R inhibitor. That is an investigator-initiated trial planning to enroll patients with high-risk, early stage TNBC before their surgery. We are also hoping to introduce novel ADCs to treat to TNBC.

What efforts is Cedar-Sinai making to improve access, awareness, and assistance for patients with breast cancer?

In the past several years, Cedars has been really wanted to reach beyond [our Los Angeles] location. Recently, Huntington Hospital joined Cedars-Sinai. Huntington has multiple locations in Southern California, so we wanted to help other indigent populations get breast cancer screening going. Cedars-Sinai also takes care of patients from the Breast and Cervical Cancer Treatment Program, which is a California government—funded project for helping patients who lack insurance.

At its traditional locations, Cedars-Sinai has been doing a good job in screening patients to get to surgery early. Before I joined Cedars-Sinai, [colleagues] told me that I may not have all these metastatic patients there. This may not be true, but they are currently doing a good job in screening patients.