Efforts to Explore Current Therapeutics in Earlier Treatment Lines Continue Across Breast Cancer Subtypes

Christie J. Hilton, DO

Research in breast cancer is focused on evaluating available antibody-drug conjugates (ADCs) and oral selective estrogen receptor degraders (SERDs) outside of the metastatic setting, which could greatly improve patient outcomes in HER2-positive and triple-negative disease, according to Christie J. Hilton, DO.

“The hope is that [we can] eventually move some of these great agents that we found in the metastatic setting into the earlier setting,” Hilton said following an OncLive^® State of the Science Summit™ on breast cancer, which she cochaired. “[This might result in] less metastatic disease, and less women relapsing.”

In the interview with OncLive, Hilton detailed key topics discussed by herself and her colleagues at the meeting, including the evolving role of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in HER2-positive breast cancer, and the potential to de-escalate therapy in early-stage disease. Hilton also highlighted efforts to expand current agents into earlier lines of therapy in triple-negative breast cancer (TNBC).

Hilton is an assistant professor in the Department of Medicine at Drexel University College of Medicine, and the director of Academic Breast Oncology for Allegheny Health Network (AHN), AHN Cancer Institute in Pittsburgh, Pennsylvania.

OncLive: What is the optimal sequence of therapy in the first line and beyond for metastatic HER2-positive breast cancer?

Hilton: HER2-positive metastatic breast cancer has really come a long way in the past couple of years. [In the] first line, your tried and true [approach] is a taxane along with trastuzumab [Herceptin] and pertuzumab [Perjeta]. That hasn't changed. In the past couple of years, the [standard-of-care (SOC)] second-line treatment has changed from ado-trastuzumab emtansine [T-DM1; Kadcyla] to T-DXd. That was an important update for us. In that second-line setting [results from the phase 3 DESTINY-Breast03 trial (NCT03529110)] showed that T-DXd did much better in terms of progression free survival [PFS], when compared with T-DM1. There is still a place for T-DM1, but the second-line SOC is going to be T-DXd.

T-DXd has become the new SOC in the second-line setting. What else is on the horizon for this agent?

[Researchers are] studying this compound in a lot of different settings, [including] ongoing trials in the neoadjuvant setting. Something that is very exciting is [research] looking at T-DXd in the residual disease population. We have the [phase 3 DESTINY-Breast05 (NCT04622319)] trial currently [being conducted] throughout the country. It will be very exciting to see if that makes a difference for women with relapsed [HER2-positive disease]. HER2-positive metastatic breast cancer has really come a long way, and it's a very exciting space to be in.

Regarding the presentation given by Gurleen Pasricha, MD, of Meadville Medical Center, what future efforts to de-escalate treatment are ongoing in early-stage HER2-positive breast cancer?

It's going to be exciting to see what the [results of the] ongoing [phase 3] CompassHER2 RD trial [NCT04457596] are. There is a big push to try to figure out [in which patients] we can de-escalate chemotherapy [and administer] more targeted agents, and who needs escalated [therapy] on the back end. In the next several years, my hope is that we have a handle on who [would benefit from] de-escalation and who needs more escalation. It's going to be a balancing act but very exciting.

Diane M. Buchbarker, MD, of Allegheny Health Network, discussed early research indicating that many novel oral SERDS appear effective in wild-type or ESR1-mutated breast cancer. If this signal continues, how could oral SERDs fill an unmet need for patients with endocrine receptor (ER)–positive, ESR1-expressing breast cancer who develop endocrine resistance?

Oral SERDs are a very exciting [emerging drug class] in breast oncology right now. Right now, we have elacestrant [Orserdu], which is approved in ESR1-mutated metastatic breast cancer. [In the phase 3 EMERALD trial (NCT03778931)], elacestrant was compared with SOC endocrine therapy or fulvestrant [Faslodex], with most of the patients in that trial receiving fulvestrant. It was exciting to see that elacestrant had such a large PFS improvement in comparison with fulvestrant. Some people will say [that] these women [may] still have some response to fulvestrant, and that's true. [However], if we can get an [effective] agent, and then have it be an oral agent, that's always better.

A lot of these [patients with] metastatic ER-positive breast cancers develop endocrine resistance, and [experience] progression through their first-line treatments, with either an aromatase inhibitor [AI] alone or an AI with a CDK4/6 inhibitor. It's nice to have another oral option for these women, [so we can take] out that pathway before moving on to chemotherapy. The fact that it's an oral agent that was well tolerated in the trial—most of the adverse effects [AEs] were grade 1/2—[indicates that] it does fulfill an unmet need for these women. I'm very excited about what's to come with the other oral SERDs being studied in the adjuvant setting and earlier settings of disease.

What is the current preferred approach to managing metastatic vs nonmetastatic TNBC per the presentation given by Sarah M. Miller, DO, of Allegheny Health Network?

A lot of wonderful [agents have] come out for metastatic TNBC, the first being sacituzumab govitecan-hziy [Trodelvy] from the [phase 3] ASCENT trial [NCT02574455]. [Sacituzumab govitecan] tends to be a very tolerable drug, and it had great results for women [with TNBC] that were heavily pretreated. That was a game changer for us in the metastatic setting.

The [phase 3 DESTINY Breast-04 study (NCT03734029)] that looked at patients with HER2-low disease also [provided] a great option for patients with TNBC if they have HER2 expression that is not [immunohistochemistry (IHC)] 3+ or [fluorescence in situ hybridization (FISH)] positive. Having more options for these women in the metastatic setting is amazing.

In early-stage TNBC, we know that the [phase 3] KEYNOTE-522 trial [NCT03036488] was a game changer [by showing our] ability to use immunotherapy in the neoadjuvant and adjuvant settings. TNBC has had a lot of amazing breakthroughs. Hopefully we will be able to treat women in that early-stage setting and prevent some relapses and the development of metastatic disease.

Could you expand on any trials in breast cancer that are being conducted at Allegheny Health Network?

A lot of the trials that we talked about during the session are [ongoing] at our institution, which is fantastic. We're excited to continue enrolling [patients to these studies], and then seeing what comes [from] the data. Another thing that we're doing on an institutional basis is checking circulating tumor DNA [ctDNA] in our patients with TNBC that have pathologic complete response [pCR]. The goal is to try to figure out which of those women who get a pCR might be destined to recur. Although [pCR] is a great marker in TNBC [that] tells us that those women are much less likely to recur, it's not 100% [accurate]. That's what we're working on right now.

I'm excited to look at those preliminary data and see if we can detect who's destined to recur and who isn't. That might help us to determine who should be escalated [on therapy], [and if] there is a population of pCR patients that should be escalated in that adjuvant setting, instead of just observed.