Real-World Data Could Help Inform Treatment Sequencing Decisions in HR+/HER2- Breast Cancer

Megan Kruse, MD

Emerging data surrounding sacituzumab govitecan-hziy (Trodelvy) and evolving knowledge of CDK4/6 inhibitors, such as ribociclib (Kisqali), palbociclib (Ibrance), and abemaciclib (Verzenio), have presented clinicians with additional questions regarding sequencing of treatments in hormone receptor (HR)–positive, HER2-negative breast cancer, according to Megan Kruse, MD, who added that examining real-world data could also inform sequencing, particularly for CDK4/6 inhibitors.

“In order to be the best provider that you can in the breast cancer space, staying on top of the literature, plus keeping a running tally of necessary biomarkers and how they influence sequencing at key points, are the most important parts of what we do today in [practice],” Kruse said in an interview with OncLive^® following an Institutional Perspectives in Cancer (IPC) webinar on breast cancer, which she chaired.

In the interview, Kruse, discussed the evolving treatment landscape in HR-positive, HER2-negative breast cancer, how the approval of fam-trastuzumab deruxtecan-nxki (Enhertu) has affected sequencing choices in HER2-positive disease, and the importance of addressing racial disparities in breast cancer care. Kruse also detailed ongoing research at Cleveland Clinic. Kruse is a breast oncologist in the Department of Hematology and Medical Oncology at Cleveland Clinic.

OncLive^®: You discussed emerging data in HR-positive, HER2-negative breast cancer. What has been the effect of the latest data for sacituzumab govitecan?

Kruse: The sacituzumab govitecan data are brand new. When we came out of the 2022 ASCO Annual Meeting, we were interested that there was a signal of progression-free survival [PFS] benefit for the drug in [patients with] HR-positive, HER2-negative [breast cancer]. Although the magnitude of benefit was reasonable to consider use in our patients, it was not the most exciting thing. The overall survival [OS] data were not yet mature at that first interim analysis. There was no survival benefit.

Shortly after, at the 2022 ESMO Congress, we got this survival benefit. This is meaningful, because we do not see drugs in [the HR-positive, HER2-negative] space having survival benefit very frequently because patients get treated with so many medications. I hope that message comes through and is clear to [clinicians] because it bumped the priority for sacituzumab govitecan up a little bit, seeing both a PFS and OS benefit.

[The OS and PFS benefits] lead to interesting questions [regarding whether] FDA approval should move in the direction of including access to sacituzumab govitecan. Most people expect that it will, and the drug is already being included in National Comprehensive Cancer Network guidelines. Where do we position it and how do we use it, especially for those patients that also fall into the HER2-low bucket and may be candidates for trastuzumab deruxtecan? This is key information that should not get lost in the shuffle.

I wanted to highlight [sacituzumab govitecan] because with so many of these conferences being virtual, it is challenging to always pick out key, important concepts. For me, this was one of them.

What effect has survival data with CDK4/6 inhibitors had on the treatment landscape?

There is a lot of interpretation of this first-line, metastatic space [for CDK4/6 inhibitors] in combination with an aromatase inhibitor [AI] that we do not know what to do with yet.

What I am referencing there is the fact that we have OS positivity for ribociclib in combination with an AI. [We also had] a negative study for palbociclib in combination with an AI. There is also a study with abemaciclib and an AI that has not yet met statistical significance, but the trend looks like it is going to meet it at some point in time with subsequent follow-up.

These data lead us to question what to do with [CDK4/6 inhibitor] selection, knowing that in the years since these drugs have been approved, [we have viewed them as] all equivalent in this space. [Clinicians would] make their treatment selection based on patient preference and adverse effect profile. However, [are these agents equivalent]? There may be some more helpful information that comes out [to answer these questions].

The investigators for the [phase 3] PALOMA-2 study [NCT01740427] are looking to get at some of that missing data, including survival follow-up data, that was incomplete in the palbociclib arm vs the control arm to flesh out that information and see if we can get a better answer. That is going to be crucial.

Currently, I am not recommending that we change any patients from their agent if they are benefiting. We all have patients that experience long-term palbociclib benefit. However, [emerging data] make me stop and think about it a little bit more when I am selecting an agent for a patient who is newly diagnosed with metastatic disease. That is the most interesting part of the CDK4/6 inhibitor story. We need to figure out what the clinical implications are.

How do findings from the phase 2 MAINTAIN trial (NCT02632045) of ribociclib following disease progression in patients with HR-positive, HER2-negative disease fold into these understandings?

The MAINTAIN trial is interesting because [a theme] across all the presentations from our [IPC event] was that sequencing of agents is a challenge. I love that MAINTAIN tries to get at some of those sequencing questions to address what we do in real-world practice. The trial dovetails nicely with the idea that we do not know what to do with the OS results for palbociclib in the first line, because most of the patients that were included in the MAINTAIN study did receive palbociclib in the first line. Is there something about the benefit of ribociclib in the second-line space in combination with different endocrine therapy that is making up for something that palbociclib doesn’t do in the first-line space?

[The MAINTAIN trial] is hypothesis generating, though it needs more follow-up. I want to see the MAINTAIN design be flushed out with more patients who either started on ribociclib or started on abemaciclib, then see if the results hold true switching to a different CDK4/6 inhibitor [in the second line]. This may be a place where we have to go to the real-world data to get a sense of what those answers are, because it’s going to be hard to do this in a randomized fashion every time.

My practice was one of not using a lot of sequential CDK4/6 inhibitors, and the MAINTAIN data made me rethink that. I have started to talk to patients who received palbociclib in the first line [about] switching to ribociclib along with a different endocrine therapy in the second line.

Halle Moore, MD, of the Cleveland Clinic, spoke on the evolving landscape of treatment with antibody-drug conjugates and kinase inhibitors in HER2-positive breast cancer. Based on the data shared, what is the consensus in terms of sequencing?

For HER2-positive metastatic breast cancer, the answer to sequencing in the first and second line seems clear to me. I would say it is going to be hard to challenge [phase 3] CLEOPATRA trial [NCT00567190] data in the first line for pertuzumab [Perjeta] plus trastuzumab [Herceptin]. There are additional trials in the works to look at that question, though these data have not been challenged for a long time.

For the second line, we have many options. The data from the [phase 3] DESTINY-Breast03 trial [NCT03529110], comparing ado-trastuzumab emtansine [Kadcyla] vs trastuzumab deruxtecan, are crucial and show us that trastuzumab deruxtecan is the clear winner in that comparison. The PFS differences were so impressive that when I start thinking about how to sequence therapy for those patients [in the second line], I am looking for the patients that might not be a candidate for trastuzumab deruxtecan, rather than assuming some of them would be better candidates for trastuzumab emtansine.

There are some quality-of-life data that show that patients do have a better, longer preservation of quality of life with trastuzumab deruxtecan compared with trastuzumab emtansine. When talking to providers, it seems like the biggest hurdle is overcoming the perception that trastuzumab emtansine is better tolerated than trastuzumab deruxtecan. [That perception] may influence treatment decision making. Looking strictly based on efficacy, the second-line space has become a lot clearer with the data from DESTINY-Breast-03.

There is still the question of what to do for patients that may be candidates for the [phase 2] HER2CLIMB trial [NCT02614794] regimen of capecitabine, tucatinib [Tukysa], and trastuzumab, particularly for those patients with brain metastases. I am still thinking about that regimen in the second line as a potential preferred option. We have OS data from that study that are encouraging, particularly for those patients with active brain metastases.

What is interesting in the follow-up literature has been that it seems there is a good signal of central nervous system benefit for trastuzumab deruxtecan, muddying the waters in that second-line space. Currently, the decision tree for me is that for patients without brain metastases, I am leaning towards trastuzumab deruxtecan, and for patients with brain metastases, I'm leaning towards the tucatinib-containing regimen.

Once you get to third line and beyond, it gets a lot tougher. If a patient received trastuzumab deruxtecan, the natural inclination will be to use the tucatinib regimen in the third line and vice versa. However, we also have other great treatment options, with trastuzumab emtansine being one of them in that third line and beyond. We may have gotten clarity [on sequencing] in the first and second line, and a little bit in the third line, and then it becomes much murkier.

Erin Roesch, MD, of the Cleveland Clinic, discussed new strategies in the neoadjuvant and metastatic settings for triple negative breast cancer (TNBC). How are you navigating what data are currently available in this space?

When evaluating patients with TNBC in the early stage, we have shifted our practice to consider most of these patients candidates for neoadjuvant therapy, largely because of the data that Dr Roesch presented, showing that immunotherapy improves outcomes for patients who are eligible for the [phase 3] KEYNOTE-522 trial [NCT03036488]. This involves thinking about our patients with 2 cm and above tumors, as well as lymph node–positive cancers.

We are shunting a lot of our patients with TNBC to a neoadjuvant treatment route, largely because of the availability of immunotherapy in that space, and we do not yet know that adjuvant immunotherapy will have the same effect. We will get that data within the next couple years to figure out if patients who are not exposed in the neoadjuvant setting will still be able to get immunotherapy in the adjuvant setting and have it make a difference. For right now, knowing that this is the only place that they can get immunotherapy, it is important to assess a patient’s candidacy for it early on.

Regardless of the immunotherapy, we still do have the option to optimize treatment based on neoadjuvant response with either adjuvant capecitabine or an adjuvant PARP inhibitor for patients who are BRCA positive. When I talk to patients about the decision to receive their systemic therapy before or after surgery, this is what I’m focusing on. It is the ability to know how well the treatment works and the ability to adapt the treatment if we do not get the response that we are looking for. Immunotherapy plays a large role in that.

Tiffany Onger, MD, of the Cleveland Clinic, discussed disparities in breast cancer and highlighted some of the work that is being done to close that gap. Could you speak to the work being done to address these disparities?

This presentation on health disparities in breast cancer, specifically related to race, was interesting. It makes us challenge our assumptions of how we best care for different segments of our patient population. One of the key messages from her presentation was that disparities come in all different shapes, sizes, and forms.

We have to have flexibility in the way we deliver our care. That is particularly highlighted with the work that Dr Onger has done in delivering breast cancer screening for our homeless or at-risk, housing-insecure patient population. This project has been successful in terms of getting screenings accomplished. There have been some breast cancers detected through that screening process. Thankfully, those patients have now been plugged in for treatment.

What is most exciting about that is not only the benefit for patients seen in real time, but the fact that we can think about novel approaches to how we deliver care and the trials that can be designed to help deliver care in different ways. Without having someone who is interested in that and recognizing where our gaps and problems are, it is hard to get that work done. I am excited that Dr Onger is bringing her clinical focus and academic focus to the disparities space in our breast cancer group.

Is there any planned or ongoing research at Cleveland Clinic that you would like to highlight?

Ongoing breast cancer research at Cleveland Clinic is focusing on many different spaces. However, some of the most exciting spaces have to do with our ability to tailor treatment for subgroups within the breast cancer population. Something that I think a lot about is how we best deliver care to our patients with invasive lobular cancer.

We know that these patients generally fall into the group of HR-positive, HER2-negative or HER2-low disease. However, there are some different aspects of the way that their disease presents, whether it is in the early stage in terms of how it looks on imaging, the response to systemic therapy, and the recurrence patterns. We are trying to get a sense of how to approach each of those different peculiarities of how invasive lobular cancer behaves. We are working on some concepts to improve the neoadjuvant treatment approach for these patients and improve the detection approach for these patients. We are also looking for recurrence in a more detailed and streamlined way.

G. Thomas Budd, MD has spearheaded an effort [at Cleveland Clinic] for a TNBC vaccine. That trial is ongoing right now for patients who are survivors of TNBC, and they are getting this vaccine to try to prevent recurrences. That trial will be expanding into more of a prevention setting for patients with high-risk family histories or known genetic mutations that may put them at risk for TNBC.

Further, Dr Onger will continue to focus her work on breast cancer disparities of all kinds to create some clinical trials that will hopefully give patients better treatment approaches and better follow-up approaches.

How do meetings such as this IPC help provide updates coming out of bigger conferences?

This program highlights how rapidly the standards of care and treatment options in the breast cancer world are progressing and growing. We saw presentations that highlighted both treatment of curative intent, early-stage breast cancer, and the metastatic setting that are novel. This variety just shows that the sharing of knowledge and our ability to regroup after big conferences to distill down the key points is important.

Moreover, it highlights the fact that biomarkers are important. Much of what we talked about is contingent on those foundational biomarkers of estrogen receptor, progesterone receptor, and HER2. However, you also hear more and more about targeted therapies, such as using Ki67 as a biomarker. We did not touch the new HER2-low indications in the space because that is a whole topic unto itself. Much of these treatment algorithms that we are talking about take into account things such as genetic mutations.