New Findings in Breast Cancer Trials Call for Restructuring of Disease Subtypes

Emerging therapies, such as ado-trastuzumab emtansine (Kadcyla), fam-trastuzumab deruxtecan-nxki (Enhertu), and CDK4/6 inhibitors are revolutionizing treatment across breast cancer subtypes, according to Gregory Vidal, MD, PhD. Vidal noted that distinguishing HER2-low as a separate form of the disease can help broaden the treatment landscape for this population.

“The future [of breast cancer] is bright,” Vidal said in an interview following an OncLive^® State of the Science Summit™ on breast cancer, which he chaired. “We are definitely going to have new therapies in our arsenal, and we are going to need to think about how we consider breast cancer as a whole.”

In the interview, Vidal, a medical oncologist at the West Cancer Center & Research Institute, summarized key points from each presentation shared at the meeting, including the evolution of treatment options for HER2-low breast cancer, emerging antibody-drug conjugates (ADCs) in triple-negative disease, and the viability of HER3 as an emerging target in breast cancer. In addition, he highlighted ribociclib (Kisqali) as a potential agent in combination with hormonal therapies and explained the importance of carefully weighing the benefits of oral selective estrogen receptor degraders (SERDs) in estrogen receptor (ER)–positive, HER2-negative breast cancer.

OncLive^®: How have neoadjuvant and adjuvant breast cancer treatments been influenced by findings from the phase 3 FeDeriCa (NCT03493854) and KATHERINE (NCT01772472) trials?

Vidal: The FeDeriCa trial has not changed neoadjuvant or adjuvant care; it just provided another option, another way to use already approved drugs, so it has not changed what we do.

KATHERINE has changed what we do. [Trastuzumab emtansine], which was originally only approved for use in the metastatic setting, [was found to be active] in a subpopulation of patients, those with higher-risk HER2-positive [breast cancer]. These findings have dramatically changed how we consider that population, and we now have an option for those patients that is beyond what we have done as standard [of care]. Although [this treatment option includes] more maintenance chemotherapy, it is [a small amount of chemotherapy overall], so it has changed what we have done more than FeDeriCa has, for example.

The KATHERINE trial found that patients with HER2-low breast cancer had worse outcomes when treated with trastuzumab (Herceptin) vs trastuzumab emtansine. How do you approach the treatment of the HER2-low patient population?

Traditionally, trastuzumab-based regimens were not indicated for patients with HER2-low disease. [In this population, these treatments were no more effective than] the standard of care, which was anti-hormonal therapy or chemotherapy if they had either hormone receptor–positive or triple-negative disease.

In HER2-low disease, [the potential of] trastuzumab deruxtecan as a treatment option is certainly going to change how we consider those patients, because now we are essentially creating a different category [of breast cancer]. Having a drug that is effective in the HER2-low population also reduces the number of patients we consider to have triple-negative disease. [Instead, we consider them to have] HER2-low, ER-negative disease. It is almost like a fourth category is being created. HER2-low breast cancer [is a different category], where we can use trastuzumab or other ADCs, such as [trastuzumab deruxtecan] and even trastuzumab emtansine, potentially.

The phase 3 DESTINY-Breast04 trial (NCT03734029) investigated how trastuzumab deruxtecan performed in patients with HER2-low disease. What do these data mean for this specific subset of patients, and how might these findings help further identify patients with HER2-low disease as a targetable subset within breast cancer?

[These findings create] a different category [of breast cancer]. This categorization may become more structured if [trastuzumab deruxtecan] is also found to be active in the early setting. Right now, in the metastatic setting, [this different category is evident].

[HER2-low disease] takes after triple-negative disease, a population in which there is a large unmet need. [Trastuzumab deruxtecan is] a new drug for patients who would traditionally be considered to have triple-negative breast cancer.

Even in the ER-positive landscape, [a category of HER2-low disease], this drug has a good survival benefit. What we need to think about now is where we place that drug in the sequence. After CDK4/6 inhibitors, we are seeing a progression-free survival [PFS] from endocrine therapy [of around 3 months], and now we may see trastuzumab deruxtecan giving us a PFS of as long as 10 months in a later-line population. Ultimately, [sequencing is] going to come down to tolerability and the patient’s quality of life, and the anti-hormonal therapy certainly delivers a better patient experience.

What emerging and investigational therapies could potentially change how you treat patients with triple-negative breast cancer (TNBC), a population that is historically more difficult to treat than some of the other breast cancer subgroups?

I look forward to what the future holds. In TNBC, [these future therapies may include] more ADCs. With ADCs, we would potentially see higher responses and lower toxicities. We can probably use other drugs that are more toxic when used by themselves to elicit high efficacy. For example, at ASCO, Ian Krop, MD, PhD, [of the Dana-Farber Cancer Institute], presented data from a phase 1/2 trial [NCT02980341] studying the ADC patritumab deruxtecan [(U3-1402) in HER3-expressing metastatic breast cancer]. This agent also showed activity in TNBC.

Some ADC and immune checkpoint combinations are being studied. There are also [agents with] other targets, PI3K inhibitors, for example, [that are being explored] in that triple-negative landscape. The future looks bright for that population.

Ultimately, the unmet need [in TNBC] is finding a therapy that [produces] more durable responses. We know patients with TNBC have a good response to chemotherapy; however, that response is short. We are trying to get a drug that elicits longer and more durable responses in TNBC, so as to improve survival.

Amit Jain, MD, of The University of Tennessee Health Science Center, spoke about patritumab deruxtecan as a HER3 target. How viable is HER3 as a new emerging target in patients with breast cancer?

We knew HER3 existed. HER1, HER2, HER3, and HER4 are part of the EGF family of receptors. HER3 by itself is more of a truncated protein, so it needs to be dimerized in order to have activity, but it serves as a target.

The ADCs work by having an antibody that serves as the target and carries a payload. HER3 is expressed in over 50% of breast cancers, including ER-negative, ER-positive, and HER2-positive breast cancers. HER3 can serve as a target for an antibody that then brings along its payload, deruxtecan, which has the same payload as trastuzumab deruxtecan, which then displays activity. We have used that strategy in TNBC for drugs like sacituzumab govitecan-hziy [Trodelvy], which targets TROP-2. However, that target, as far as we know, has no activity, and that pathway itself has no impact for tumorigenesis; it just serves as a target to bring the payload to that tumor. HER3 can also serve that purpose.

S. Sameer Nasir, MD, of the West Cancer Center & Research Institute, presented on CDK4/6 inhibitors, with a focus on ribociclib. How has that agent been used in combination with different endocrine therapies in these patients?

Ribociclib is 1 of the 3 CDK4/6 inhibitors [available], and it is used in combination with either fulvestrant [Faslodex] or aromatase inhibitors. [The agent is] approved for use in the first- and second-line metastatic setting, and it is used similarly to the other 3 drugs on the market. [Ribociclib] has had a differentiation based on recent publications and presentations of overall survival [OS]; it is an active drug in combination with hormonal therapy. It [will likely distinguish] itself from palbociclib [Ibrance], which is the drug that is most commonly used in this setting.

Is [ribociclib] ultimately different [from palbociclib]? Many details still need to be recognized. First, the studies [looking at ribociclib vs palbociclib] have all recruited slightly different populations, so the OS results may reflect that.* However, ribociclib continues to have an OS benefit, and all its trials have matured results.

We are also still awaiting OS results [associated with] abemaciclib [Verzenio] in combination with aromatase inhibitors, but we know there are OS [data for abemaciclib] in combination with fulvestrant.

The issue with ribociclib is the systematic change that needs to happen in a clinic in order to use it, which is EKGs. That is the main reason why this drug has not been used in large amounts, as it probably should be. Ultimately, however, [the hope is that] once we are able to tease out the potency of these drugs with different populations, [abemaciclib plus aromatase inhibitors] will be successful [in providing an OS benefit].

Emily Miller, MD, of Messino Cancer Centers, presented on oral SERDs in ER-positive, HER2-negative breast cancer. How do you see these agents fitting into the treatment arsenal?

Oral SERDs are going to take some time to fully figure out; there are quite a few of them on the market. Unfortunately, the studies that have been conducted [with SERDs] are superiority studies, meaning they determine whether a drug is better than what is on the market.

We should be looking at noninferiority trials in this population because we know SERDs are active. The question is: Are they better than or equal to what we have on the market? Because they are an oral formulation of something that is now [also administered intramuscularly], patients will often use the oral version over the intramuscular version, because many patients do not want to get injections. Companies must start to think of their strategy when designing oral SERDs.

Ultimately, however, these drugs are going to be part of our arsenal in fighting ER-positive, metastatic breast cancer. Companies are also looking at oral SERDs in the early setting, and I am looking forward to seeing how those data pan out.

What ongoing clinical trial research in breast cancer is happening at West Cancer Center & Research Institute?

We have many of the DESTINY trials, which are being done in [those with] HER2-low and HER2-positive disease—especially in the early settings. I am looking forward to seeing those studies resolved, because [trastuzumab deruxtecan] may have activity earlier.

In TNBC, we have a few combinations [that are under exploration], such as immunotherapy and chemotherapy combinations. In patients with homologous recombination–deficient disease, we are also examining whether some drugs, mainly PARP inhibitors combined with immunotherapy, show some activity.

I am looking forward to what the future holds. Many trials that are being conducted that do not have results yet have activity and may change what we do in the future.

What main message would you like to leave colleagues with regarding all the research and emerging therapies that are currently unfolding within breast cancer?

We will need to make some systematic changes to our practices from a pathology perspective. For example, for HER2-low breast cancer, the institutions that only do fluorescence in situ hybridization testing now need to also start doing immunohistochemistry analyses. Institutions should also look at their populations of patients with HER2-negative disease and make sure that they categorize those patients with HER2-low, so that trastuzumab deruxtecan can be an option for them.

Many of the drugs that we are looking at and are so impressed with in the metastatic setting are also being examined in the early setting. The future looks bright for closing the mortality gap of patients with breast cancer. I look forward to what the future holds, and in my lifetime, we will likely make even further advances in breast cancer survival.

*Editor’s Note: Results from the phase 3 PALOMA-2 trial reported at the 2022 ASCO Annual Meeting demonstrated that first-line treatment with palbociclib (NCT01740427) plus letrozole (Femara) did not provide a significant benefit in OS vs letrozole monotherapy in patients with ER-positive, HER2-negative advanced breast cancer, missing the secondary end point of the trial.¹

Reference

Finn RS, Rugo HS, Dieras VC, et al. Overall survival (OS) with first-line palbociclib plus letrozole (PAL+LET) versus placebo plus letrozole (PBO+LET) in women with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ER+/HER2− ABC): analyses from PALOMA-2. J Clin Oncol. 2022;40(suppl 17):LBA1003. doi:10.1200/JCO.2022.40.17_suppl.LBA1003