TNBC Awareness Day: Unveiling New Findings and Developments

Daniel Carlson, DO

The treatment of triple-negative breast cancer (TNBC) continues to present complex challenges for oncologists and their patients. While Daniel Carlson, DO, explained that significant progress has been made in the space in recent years, there is still need and room for improvement.

Diagnosing TNBC has become more accurate over the years, but treatment options remain limited compared with other subtypes of breast cancer. While multimodality chemotherapy is effective, durable results are not always achieved. This is most times the case among patients with residual disease after treatment.

The emergence of immunotherapy has also brought hope for patients with TNBC, especially those with locally advanced disease. Findings from the KEYNOTE-522 trial (NCT03036488) demonstrated a significant increase in pathological complete response (CR) rates vs chemotherapy alone.1

Five-year results from the phase 3 KEYNOTE-522 trial showed that among patients treated with chemotherapy and pembrolizumab, the event-free survival (EFS) rate was 81.3% vs 72.3% in the placebo arm. This resulted in a reduction in risk for recurrence, progression, complications, or death by 37% (HR, 0.63; 95% CI, 0.49-0.81).

However, the true effectiveness of immunotherapy for metastatic TNBC treatment and for patients with residual disease continues to be investigated.

“I think that the outcomes are better with the advent of immunotherapy, but we still have a considerable area of unmet need where we are not achieving pathologic CRs,” explained Carlson, DO, in an interview with Targeted Oncology^TM.

Despite the challenges, ongoing efforts aim to find better solutions in the TNBC space.

In the interview, Carlson, DO, breast medical oncologist, clinical investigators, Allina Health Cancer Institute, delved into the complexities of TNBC, highlighting the current space and future possibilities.

Targeted Oncology: What are some of the biggest challenges in diagnosing and treating triple-negative breast cancer?

Breast Cancer - Female Anatomy - pain concept: © peterschreiber.media - stock.adobe.com

Carlson: Diagnosis-wise, we have gotten much better. The challenge now turns into how do we treat this effectively? The vast step forwards that we have made in breast cancer, when we first started treating with multimodality approaches, has come significantly forward. It certainly has in triple-negative as well, but compared with hormone receptor-positive or HER2-negative disease or the hormone receptor-negative/HER2-positive space where we have made tremendous strides, triple-negative has not to the same degree. There are significant challenges that still persist, particularly now in the advent of the immune therapy age with regard to patients that still have residual disease, where they have significantly higher propensity for relapse, and especially still in the metastatic de novo stage.

How has the evolving understanding of the biological characteristics of triple-negative breast cancer impacted treatment options?

The biological behavior of that, relative to other types, is different. Contrasting with hormone receptor-positive disease where we typically are talking about a biologically behaving disease that is not particularly chemosensitive and much more sensitive to hormone therapy typically, and then comparing that with HER2 disease where we have a significant chemo sensitivity, but not to the degree where before the advent of monoclonal antibodies directed against HER2 where we were seeing significantly durable responses. Triple-negative is something where we know, going back even to the 90s, that multimodality chemotherapy compared with single-agent chemotherapy certainly is effective. The sensitivity to chemotherapy is significantly more so with regard to the biological behavior of triple-negative disease.

However, the results that we saw comparing just chemotherapy alone in the triple-negative space relative to other types of breast cancer, as well as other types of cancer in general, did not necessarily lead to great outcomes in terms of durability. One of the exciting things now is that in the era of immunotherapy, which has moved the ball forward considerably, we are seeing significant increases in pathologic CRs and event-free survival, which is exciting.

What have been some of the biggest advancements in the TNBC space over recent years?

In the locally advanced setting, because this, unfortunately, is not applicable for the early-stage patients where there is kind of a T1c patient who is node negative, [we are] still going to be giving them chemotherapy. They are not going to be given immunotherapy. But outside of that if [we are] talking about positive nodal disease, the advent of KEYNOTE-522 in locally advanced disease has been phenomenal in terms of outcomes. Pathologic CR was initially reported at almost 65% in the original 2020 paper vs about 50% in the original article in the control arm. That is about a pathologic CR that's about 14% better and that's huge.

The article that was published in 2020, which was the additional data, [showed that] the event-free survival, which had been about a 5% benefit in the original paper, is now trending up. The curves are separating the further out that we go in terms of the data for event-free survival. We are talking about a situation where I believe it is about 85% vs around 77%. [Also], the durability with these is pretty significant.

One of the challenges and 1 of the things that I talk about with patients often in the clinic is that a lot of our data is with regard to patients that still have residual disease. We are talking about a space where we are improving outcomes, but there still is a considerable amount of patients who are not achieving a pathologic CR still. One of the problems now is that a lot of our data, with regard to how we approach residual disease, is not comparing apples to apples because the data is pretty much confined to the chemotherapy utilization in the triple-negative space. I think that the outcomes are better with the advent of immunotherapy, but we still have a considerable area of unmet need where we are not achieving pathologic CRs and the ability to use the data that we have for how to go forward with pathologic CRs that are not being achieved in patients that still have residual disease.

Are there any promising trials or emerging therapies specific to triple-negative breast cancer that you are particularly excited about?

With regard to residual triple-negative disease in particular, based on the ASCENT trial [NCT02574455], which was originally published in 2021, looking at sacituzumab govitecan [Trodelvy], there is an ASCENT-05 [NCT05633654] trial that is currently enrolling. It is a phase 3, randomized, controlled trial in patients that still have residual triple-negative disease. They are randomizing those patients between the sacituzumab and pembrolizumab [Keytruda] arm, which is the experimental arm, and then the physician's treatment choice on the other arm. I think that that is promising, potentially because we know from the ASCENT data in the metastatic setting, that the patients that were fairly heavily pretreated with greater than 2 prior lines of chemotherapy. In the ASCENT trial, they saw significant improvements in terms of both median [progression-free survival (PFS))]and median [overall survival (OS)]. The PFS benefit was significant, the hazard ratio on that was very impressive, and then the median overall survival also had an impressive hazard ratio as well.

One of the problems though is that when we compare those data with patients in the metastatic hormone receptor space, for instance, PFS and OS [are] significantly shorter in those other areas. There is a large area for improvement of the interesting questions that is potentially going to be addressed in ASCENT-05, or at least we will get an additional perspective on this. In the metastatic untreated space for triple-negative, we are typically using pembrolizumab plus chemotherapy based on the KEYNOTE-355 trial [NCT02819518], which was also published in 2022. That one is important because up until that point, we had been using the IMpassion130 [NCT02425891] data before the FDA took that away from us and then revoked that approval.

The interesting aspect of the KEYNOTE-355 data when we compare that vs the KEYNOTE-522 data, so talking about metastatic vs the locally advanced setting, is that the PD-L1 expression does matter considerably currently in the metastatic triple-negative setting because the cohorts in the KEYNOTE-355 data, we were looking at PD-L1 expression based on the [combined positive] scores [CPS]. As reported, the only patients that seem to derive benefit where they were meeting their primary end points, as well as secondary end points, were in the CPS greater than 10. For a lot of other types of cancer, we are seeing benefit in patients that have a PD-L1, 1% or more, that not being the case here.

In contrast, in KEYNOTE-522, PD-L1 does not matter. In the locally advanced setting, they are still deriving benefits from the addition of immunotherapy. As far as we know, that distinction has not particularly been significantly looked at in terms of answering. Is the addition of pembrolizumab to additional agents something that we could potentially benefit from in this situation in residual triple-negative disease with pembrolizumab? We have data from KEYNOTE-522 saying that pembrolizumab in this situation, when it's in the nonmetastatic setting, does not seem to matter what the PD-L1 expression is. In that regard, given the fact that the original ASCENT data was quite impressive, although short-lived in terms of the difference that it demonstrated in terms of the PFS and OS, in addition to combining that with pembrolizumab in patients that have the locally advanced disease holds the potential to be quite promising.

With limited targeted therapies available in the space, how do you personalize treatment plans for your patients?

Looking at other targets is something that is important. There's the GLORIA study [NCT03562637] right now looking at [globohexaosylceramide] potentially as a target as well. But I am short of the trials, which are right now, mostly in phase 1 or phase 2. But sequencing is challenging. As we mentioned before, most people in the metastatic setting are using the KEYNOTE-355 data and they are potentially then testing for BRCA, which is something important in triple-negative disease. We had the original OlympiAD [NCT02000622] data in 2017 and then the BRCA data in 2018, and so we know there is a PFS benefit in the [poly-ADP ribose polymerase (PARP)] inhibitors in BRCA-mutated patients. Then with the OlympiA [NCT02032823] data in 2021, there was a benefit in invasive disease-free survival as well. That situation, in both patients that have received neoadjuvant or adjuvant therapy in the triple-negative space, is impressive.

Genetics plays a huge role in triple-negative, particularly with patients who have a BRCA mutation. As it stands, less than 10% of patients have those, so certainly an area of unmet need that we do need to explore different targets for because particularly given that KEYNOTE-355 is limited in the metastatic sphere to patients with a CPS above 10, that is a considerable amount of patients that are not going to be meeting and are not gonna be deriving benefit from that. As we have known for a long time, the patients that are treated with chemotherapy in the de novo metastatic setting do not necessarily do well. [They] have a slight benefit in response rate when using multimodality chemotherapy when combined, but [we] still are not seeing differences in terms of overall survival vs single-agent chemotherapy at all, which is quite challenging.

One of the exciting aspects, with regard to targets in the triple-negative sphere, is the data from the DESTINY-Breast04 trial [NCT03734029], also published in 2022, looking at HER2-low [breast cancer]. Because a lot of the triple-negative patients are not going to fit into that HER2-low sphere, in patients that have had prior chemotherapy, the use of [trastuzumab deruxtecan (Enhertu; T-DXd)]in this sphere certainly is coming into its own. The question of sequencing, especially vs sacituzumab, is a difficult question for now.

Typically, when I'm talking with patients about this, it comes down to tolerability and the [adverse] effect profile personally. I see a lot of patients as a second opinion and I think everybody's an individual person. If significantly worried about issues with [interstitial lung disease], which can be quite severe in the [patients getting] T-DXd, that might be something to steer away from. If concerned about neuropathy or significant neutropenia, then sacituzumab also might be something to kind of stay away from. It definitely is an area of unmet need that I am hopeful we will be working towards answering in the future, because this certainly is something where we still, again, have considerable area for improvement.

What do you hope to see in the future of triple-negative breast cancer research?

In the HER2 sphere, the advent of antibody-drug conjugates has been phenomenal now that we have sacituzumab and T-DXd in our armamentarium. I think 1 of the problems is going to be identifying unique targets and going after them. The fact that we do not have more, I think, is challenging given that the patients we are typically dealing with in the triple-negative realm are patients that do not progress over a long period of time. Usually it is pretty quickly after they have exhausted their options.

I think trial enrollment is challenging in that regard, outside of agents that are particularly useful. Not only are we needing new targets, but also being cognizant of the [adverse] effect profile of those targets is something. I think that is not necessarily limited to triple-negative, that is almost anything in the entire oncology realm too. Certainly, it is a much better time. I don't mean to leave people with the sense that things are kind of hopeless as it certainly is much better in terms of triple-negative, in my perspective, than it was even 20 years ago, but we still can do considerably better as well.

What resources could you recommend for patients in this space to help manage their anxiety?

In my de novo metastatic patients, all of them see palliative medicine, which are extremely helpful for both dealing with [adverse] effects as well as managing symptoms. We also have had significant depth in terms of clinical behavioral psychology too, which is also helpful. I was just seeing a second opinion earlier this week from about 3 hours away and having this discussion with patients is psychologically very devastating. In my experience, having a clinical psychologist is very helpful. We also, at our program and when I was in training, had an extremely robust nurse navigation program too, which is unbelievably helpful for patients with breast cancer. They are kind of like the chauffeur, so to speak, of making sure that everything is being done appropriately, and that everything is being followed through on and that imaging studies are being done when they are supposed to be, and that they are making these meetings with other services if we are needing additional input on how they are doing.

What message would you like to share with community oncologists about improving outcomes for these patients?

This field is rapidly changing, so keeping up with things is very important. The pace with which things are changing in the triple-negative realm as well, given the fact that we talked about several trials, most of which have been reported in the last 4 years. I do see patients who are sent from other people, and they may not be getting some of these therapies that we would otherwise be utilizing in the normal situation for locally advanced or metastatic de novo diagnosis. It is worth the time to familiarize yourself with it. If it is something where patients are uncomfortable or they are anxious, I find that it is helpful in a number of patients [to get] second opinions as well, given the complexity of these cases. When they are treated at a center that has trials available as well, sometimes that can be advantageous on a number of levels to not just know what the standard-of-care is, but certainly the treatment, at the community level, is the cornerstone in the bedrock for oncology. I think that the challenge with triple-negative relative to other breast subtypes is just the considerable amount that we still have in order to get to a better place. Triple-negative disease means that we are going to be utilizing trials for some time.

What unmet needs still exist in this space?

An area of significant unmet need is a triple-negative disease with [central nervous system] metastases. That currently has dismal outcomes. I am not particularly aware of a lot currently to try to address that. One of the problems with that is, particularly in my experience, the patients go downhill so quickly that trial enrollment is a significant challenge. That definitely remains an area of unmet need as well.

With the advent of the widespread utilization of immunotherapy, which is going to continue to be an important aspect and bedrock for treatment for triple-negative disease, 1 of the challenging aspects is for patients that do not make it through the entire treatment. The KEYNOTE-522 regimen is kind of a beast. It is 6 months of therapy, 4 cycles of 3 agents, then 4 additional cycles of three other agents besides the pembrolizumab staying the same. The immune toxicities that we can incur with that can be pretty harsh. Most of them are fairly easy to deal with when at a center where [one has] an experienced endocrinologist and experienced hepatologist. That does become more challenging when doing it on your own though, and particularly for patients that are not educated about what to expect with that. Typically, that is something that we go into great detail about.

Even though the rates with [immunotherapy] adverse events are not horrendous, they certainly are higher than they are with chemotherapy backbones when we compare them with the placebo arms in any of those trials. Being able to be managing these in both a timely manner and in a manner in which hopefully, the patients are able to continue with the therapy, in the case of a lot of the thyroid abnormalities that we see is important because 1 of the things that I do see a lot is people who have to quit early and then they are not achieving pathological CRs. Then we are kind of in a situation of this, what do I do? Do I continue with what was not finished after everything is stabilized or do we go off of the data that is not from the area of immunotherapy to begin with. That is also challenging. Managing the [immunotherapy] toxicities from some of these and being familiar with them is extremely important for breast medical oncologists as well.

REFERENCE:

Schmid P, Cortés J, Dent RA, et al. Pembrolizumab or placebo plus chemotherapy followed by pembrolizumab or placebo for early-stage TNBC: Updated EFS results from the phase III KEYNOTE-522 study. Ann Onc. 2023;34(S2):S1256-S1257. doi:10.1016/j.annonc.2023.10.008.