Systemic Therapy Shows Increasing Promise for CNS Metastases in Breast Cancer

Nancy U. Lin, MD

As the treatment of patients with central nervous system (CNS) involvement across breast cancer subtypes has come to the forefront of current research efforts, the role of systemic therapy vs the long-time standard of care, radiation therapy, continues to evolve, according to Nancy U. Lin, MD.

“Brain metastases are an increasing problem, particularly in our patients [with] HER2-positive and triple-negative disease, but they also affect our endocrine receptor [ER]–positive patients as well,” Lin said in an interview following an OncLive^® State of the Science Summit™ on breast cancer, which she co-chaired.

In the interview with OncLive, Lin provided clinical insights on the treatment of patients with breast cancer brain metastases and discussed the advantages and disadvantages of systemic therapy vs radiation therapy for this population. Lin also expanded on key topics discussed by her colleagues at Dana-Farber Cancer Institute at the meeting, including challenges and unanswered questions regarding the optimal sequencing of antibody-drug conjugates (ADCs), post-CDK4/6 inhibitor options in hormone receptor–positive breast cancer, and several emerging therapeutics in HER2-positive breast cancer.

Lin is the associate chief of the Division of Breast Oncology at Dana-Farber Cancer Institute, and Susan F. Smith Center for Women’s Cancers. She is also the director of the Metastatic Breast Cancer Program and the Program for Patients with Breast Cancer Brain Metastases, as well as a senior physician and associate professor of medicine at Harvard Medical School in Boston, Massachusetts.

OncLive: In what scenarios would you select systemic therapy over local treatment for patients with breast cancer who have CNS metastases?

Lin: [Deciding] when to consider systemic therapy and defer radiation therapy is an area in evolution. For years, radiation therapy has been the standard of care for most patients with brain metastases. We sometimes offer surgical resection for patients who have very symptomatic or large lesions, or where there's a diagnostic dilemma.

The role of systemic therapy has been evolving. It's evolved furthest in patients who have HER2-positive breast cancer brain metastases, where we do have several options with decent CNS response rates and reasonable progression-free survival [PFS]. That raises the question of whether we can use some radiation-sparing approaches, [because] as patients live longer there are concerns about late toxicities of radiation therapy.

In my patients with HER2-positive disease, I try to avoid or push off the need for whole brain radiation therapy [WBRT] as long as it is reasonable. For example, if a patient has never had a tucatinib [Tukysa]-based regimen or fam-trastuzumab deruxtecan-nxki [Enhertu], I might offer those regimens prior to radiation in hope that the response rate will be high enough to push off the need for radiation.

How do updated results from the phase 2 HER2CLIMB trial (NCT02614794) demonstrate the benefit of systemic therapy in this patient population?

HER2CLIMB demonstrated the general principle that systemic therapy could substantially extend overall survival [OS] in patients with both treated and stable, as well as active brain metastases. [This is] the first time that a randomized trial in breast cancer has shown that effect. In randomized trials of WBRT vs stereotactic radiosurgery [SRS], for example, even though there was better intracranial control with WBRT, there was no difference in OS compared with SRS. That's why SRS is our standard for patients who present with a limited number of metastases.

[In HER2CLIMB], we saw a doubling of 2-year OS with the addition of tucatinib to trastuzumab [Herceptin] and capecitabine [Xeloda]. These are very important results, because they really point to the potential for systemic therapy to affect substantial changes in patient outcomes.

What other systemic options exist for patients with HER2-positive breast cancer brain metastases, and how do you select between them?

Another option that we have seen activity with is trastuzumab deruxtecan. We've seen this in the context of some of the registrational trials, although those trials did not include a substantial number of patients with active brain metastases. We've also seen it in small, prospective trials, as well as institutional experiences in patients who have active brain metastases. The reports have mostly come from patients with HER2-positive disease at this point, although we've seen some activity in HER2-low patients as well. Trastuzumab deruxtecan is a systemic option that we reach for in HER2-positive [brain metastases], and, to some extent, in patients with HER2-low breast cancer brain metastases.

Other chemotherapy regimens and ADCs are useful [in this setting]. Ado-trastuzumab emtansine [Kadcyla] also has activity in patients who have HER2-positive breast cancer brain metastases. We've [also] seen some of the newer targeted agents, including abemaciclib [Verzenio], alpelisib [Piqray], or PARP inhibitors demonstrate limited evidence of CNS activity. By limited, I mean that the studies have been small.

What unmet needs exist regarding treatment for brain metastases in patients with breast cancer?

It's a very subtype specific. Although we have options for patients with HER2-positive disease, patients do progress through them, so we still need more. For patients who have HER2-negative disease, whether it's estrogen receptor [ER]–positive or triple-negative, we are not nearly as far along. We need to develop better systemic options so that patients can move from one efficacious option to another as the disease progresses. We don't have that sequence the way that we would like for patients with HER2-negative brain metastases.

The other area of significant unmet medical need is patients with leptomeningeal disease. We still have a lot of progress to be made, [because] OS remains quite poor.

Regarding the presentation given by the event’s co-chair, Sarah Sammons, MD, of Dana-Farber Cancer Institute, what major controversies exist regarding the use of CDK4/6 inhibitors in the first line?

The question is whether the 3 commercially available CDK4/6 inhibitors, palbociclib [Ibrance], ribociclib [Kisqali] and abemaciclib, are functionally equivalent, or whether they produce a clinically important difference in outcomes. If we look at metrics like PFS, [outcomes] look comparable and almost superimposable between the 3 CDK4/6 inhibitors across randomized trials. However, if we look at OS, we see that abemaciclib and [particularly] ribociclib have demonstrated OS advantages, whereas palbociclib has not. The debate has been why that is. Is there a true biologic difference between the drugs such that palbociclib is not as good of a drug? Or is there a play of chance, because there is some chance involved with any trial results? Is it an issue of inadequate follow-up? In some of the palbociclib trials, for example, we've seen some loss to follow-up, and perhaps that might explain a loss of power to detect OS differences.

The truth is that these trials are done at this point, and the data are what they are. We can't go back and [get more] follow-up of those patients. We must take the data as they are. [As it stands], ribociclib has the strongest OS data. Abemaciclib also has OS data, and palbociclib does not. In practice, I'm not switching patients [to another drug] if they are currently on palbociclib and benefiting. For patients who are newly starting [treatment], I'm generally choosing either ribociclib or abemaciclib.

As discussed in the presentation given by Ana Garrido-Castro, MD, of Dana-Farber Cancer Institute, what questions remain regarding the optimal sequencing of ADCs in breast cancer?

The ADC field has really exploded. There are many investigational ADCs, including ones that target HER2 and TROP2, which we're familiar with, but [there are] also ADCs that have several other targets and payloads. In general, ADCs have proven to be a robust platform where we've seen activity in highly treatment-refractory patients.

One of the topics that Dr Garrido-Castro addressed is this issue of sequencing ADCs. That's going to be the next area of intensive clinical research because it's so important in our clinical practice. Does it matter in which order one sequences ADCs from one to another? Can we predict whether the second ADC will work based on a liquid or tumor biopsy [conducted] after the first ADC has stopped working? These are important and practical questions. Right now, in the absence of those data, we're just playing it by ear.

In my practice, I am sequencing patients from trastuzumab deruxtecan to sacituzumab govitecan-hziy [Trodelvy], or vice versa. However, we would all like to know and have better data on what our expected outcomes would be [for the sequencing of trastuzumab deruxtecan and sacituzumab govitecan], and whether there are predictors of who might benefit [from treatment with a] second and eventually third or fourth ADC when they are available.

Paolo Tarantino, MD, and Erica L. Mayer, MD, MPH, both of Dana-Farber Cancer Institute, discussed post-CDK4/6 inhibitor therapies in ER-positive breast cancer. Based on their discussions, how have post-CDK4/6 inhibitor strategies evolved in recent years?

The sequencing and [treatment] options for patients who have ER-positive metastatic breast cancer [following a CDK4/6 inhibitor] have become quite complicated. It used to be very straightforward. It used to be endocrine-based [therapy] and a CDK4/6 inhibitor usually [followed by] an everolimus [Afinitor]-based combination or an alpelisib-based combination based on PIK3CA mutation status, and potentially the use of fulvestrant [Faslodex] monotherapy. That has clearly evolved.

There was a [phase 3] study called SONIA [NCT03425838] presented at the 2023 ASCO Annual Meeting which raises the question of whether we have to be giving first-line CDK4/6 inhibitors to all [of our patients]. In our discussion, our group concluded that we're generally still going to be recommending a first-line CDK4/6 inhibitor, but perhaps less dogmatically. With patients who don't want the additional toxicity, are frail, or have other reasons, we will be more reassured in waiting [to give] a CDK4/6 inhibitor. So even that first-line setting is a little shaken up.

After progression on a CDK4/6 inhibitor, [one key] controversy is: should we be reusing CDK4/6 inhibitors? We have data from the randomized phase 2 MAINTAIN trial [NCT02632045] that suggested that switching to fulvestrant and ribociclib after an aromatase inhibitor and palbociclib was beneficial. [Notably, palbociclib is] what most of the patients in the trial had in the first-line setting. Whether this really applies to patients who receive first-line ribociclib and abemaciclib is unknown.

We have results from the [phase 2] PACE trial [NCT03147287], which was, generally speaking, [an assessment] of palbociclib after [prior] palbociclib. That study did not show benefit for continuation of palbociclib. Finally, we have [the ongoing phase 3] postMONARCH trial [NCT05169567], which [is evaluating] abemaciclib after a prior CDK4/6 inhibitor. The results from that study will be important. Right now, the use of CDK4/6 inhibitors after progression on a CDK4/6 inhibitor is an unsettled question.

Then there's the combination of endocrine therapy and everolimus, and there's the alpelisib combination for patients who have PIK3CA mutations. However, both drugs do carry toxicities with them, and trying to develop better options would be valuable. Finally, there is the impending approval of capivasertib, which is currently under review by the FDA. We had some discussions about where that would fall into the spectrum [of treatment options] and how we might sequence these drugs.

In the absence of optimal therapeutic sequencing data, what factors are used to select between these subsequent treatment options? When would you select continued CDK4/6 therapy vs an mTOR inhibitor or an oral selective estrogen receptor degrader (SERD)?

When considering the new oral SERD elacestrant [Orserdu], we're looking for patients with ESR1 mutations who have evidence of endocrine sensitivity. Patients who [spent] at least 6 months, if not more than 12 months, on their prior endocrine therapy tend to derive the most benefit from elacestrant and have the least early fall off on the Kaplan-Meier curves in terms of progression at the first restaging scan. As far as patients who have had less than an optimal duration of response to their prior endocrine therapy, we are often bypassing elacestrant [in favor of] another combination, whether that’s an everolimus-based combination, an alpelisib-based combination, or a clinical trial.

What emerging therapeutics for HER2-positive metastatic breast cancer do you feel have the most promising activity based on the presentation given by Adrienne G. Waks, MD, of Dana-Farber Cancer Institute?

We have seen the approval of margetuximab-cmkb [Margenza], which is an engineered antibody very similar to trastuzumab that allows for better antibody-dependent cellular cytotoxicity. The idea is that it will better unleash the immune responsiveness to trastuzumab. There was a positive trial––[the phase 3 SOPHIA trial (NCT02492711)]––although one could argue about the clinically meaningful nature of the difference in PFS [between margetuximab plus chemotherapy vs trastuzumab plus chemotherapy]. Nevertheless, there was an approval, it is an option, and we do use it for our late-line patients in combination with cytotoxic chemotherapy.

Another interesting trial that Dr Waks highlighted was the [phase 2] monarcHER trial [NCT02675231]. That trial looked at the combination of trastuzumab, fulvestrant, and abemaciclib. It was a randomized phase 2 trial, so one has to take it with some caution. What was interesting about that trial is that the [non-chemotherapy] triplet beat trastuzumab [plus] chemotherapy in the late-line setting with respect to overall response rate and PFS.

Preclinically, the combination of HER2-targeted therapy and CDK4/6 inhibition is quite interesting. Over the next year or so, we will hopefully see results of the first-line, [phase 3] PATINA trial [NCT02947685], which added palbociclib to trastuzumab plus pertuzumab [Perjeta] maintenance in the first-line setting. In terms of other interesting compounds, there are a number of novel HER2-targeted ADCs in development. We're also continuing to see ADC expansion in the HER2-positive metastatic breast cancer arena.

Are there one or two trials in the breast cancer space that are being either conducted at your institution or that you are personally involved in that you'd like to highlight?

One of the studies that we're really excited about is the [phase 2] STOP-HER2 trial [NCT05721248]. This trial is being led by Heather Parsons, MD, MPH, of Dana-Farber Cancer Institute, within the translational Breast Cancer Research Consortium. The plan is to open up to 10 sites nationally. This study is looking for patients who have had at least 3 years of disease stability on their first-line HER2-directed regimen and are still on that first-line regimen. Patients in the study elect either to stop their HER2 treatment completely or to continue the HER2 treatment. It's not a randomized trial, as patients select which group they want to belong to. Then patients agree to have scans every 3 months with research blood [samples drawn] every 3 months as well. The purpose of the study is to understand whether there's a subset of patients with HER2-positive metastatic breast cancer, historically deemed incurable, who may be able to indefinitely stop their HER2-directed therapy. It's the first study of its kind in this space, and it's exciting to test [such] a new concept.

Another study to highlight, which is not open yet but hopefully will be open soon is called the Trade-DXd study. This is being led by my colleague, Dr Garrido-Castro. This study is looking at the sequence of either trastuzumab deruxtecan [followed by] datopotamab deruxtecan [DS-1062a; Dato-DXd], or the opposite sequence. Datopotamab deruxtecan is a TROP2-targeted ADC with the same payload as trastuzumab deruxtecan. The two sequences are not being directly compared, but the idea is to understand sequencing in the setting of HER2-negative and -low breast cancer. Biopsies and blood samples are going to be collected to get at this question of the optimal sequencing of ADCs. Can we predict whether the second ADC will be effective based upon either tissue or blood biopsies after the progression on the first ADC? That is going to answer some important, practical questions and provide access to datopotamab deruxtecan as part of a clinical trial for patients who participate.