Updates From 2022 SABCS Underscore the Continued Expansion of Treatment Options in Metastatic Breast Cancer

Virginia F. Borges, MD, MMSc

Updates on CDK4/6 inhibitors in hormone receptor (HR)–positive/HER2-negative breast cancer, optimal treatment choices in the first and second line of HER2-positive breast cancer, and treatment considerations for HER2-low breast cancer presented at the 2022 San Antonio Breast Cancer Symposium (SABCS) highlighted the continuously evolving treatment paradigm across the disease, according to faculty from an OncLive® State of the Science Summit™ on breast cancer.

The event, chaired by Virginia F. Borges, MD, MMSc, a professor of medicine in the Department of Medical Oncology, at the University of Colorado (UC) School of Medicine, and a medical oncologist at the UCHealth Diane O'Connor Thompson Breast Center, Anschutz Medical Campus, in Aurora, Colorado, highlighted updates across the breast cancer landscape, including key updates from the 2022 SABCS.

Borges was joined by her colleagues:

• Peter Kabos, MD, an associate professor of medicine in the Department of Medical Oncology, the UC Cancer Center NCI-Designated Comprehensive Cancer Center
• Elena Shagisultanova, MD, PhD, an associate professor of medicine in the Department of Medical Oncology, at the UCHealth Diane O'Connor Thompson Breast Center, Anschutz Medical Campus
• Radhika Acharya-Leon, DO, an assistant professor of medicine at UCHealth Cancer Center, Highlands Ranch
• Jennifer Diamond, MD, an oncologist at the UC Cancer Center NCI-Designated Comprehensive Cancer Center
• Marie Wood, MD, the director of Breast Medical Oncology and the director of the Cancer Clinical Trials office, the UCHealth Diane O'Connor Thompson Breast Center, Anschutz Medical Campus, and Highlands Ranch Hospital

Below, Kabos, Shagisultanova, Acharya-Leon, Diamond, Borges, and Wood, summarize the main messages from their presentations.

Factors for Choosing Frontline CDK4/6 Inhibitors in HR-Positive/HER2-Negative Breast Cancer

Kabos: For CDK4/6 inhibitors [in the metastatic setting], many trials have been done. The differences [between trials] were in patients who were selected. Some [trials] were in first-line therapy, some were 2 lines or more, and some were a combination of the two.

The [phase 2 MONALEESA-1 trial (NCT01919229), phase 3 MONALEESA-2 (NCT01958021), MONALEESA-3 (NCT02422615), and MONALEESA-7 (NCT02278120) trials] have shown an overall survival [OS] benefit [for ribociclib (Kisqali)] at this point. The phase 3 MONARCH 2 trial [NCT02107703] has shown an OS benefit with abemaciclib [Verzenio], and the phase 3 MONARCH 3 trial [NCT02246621] is trending [toward an OS benefit]. The phase 3 PALOMA-2 [NCT01740427] and PALOMA-3 [NCT01942135] trials [evaluating palbociclib (Ibrance)] have not shown a benefit with OS. However, if you look at the hazard ratios for response, they are on par [with abemaciclib].

I would highlight the 3 agents that we have in front of us when we're deciding [on treatments] with our patients [with HR-positive/HER2-negative breast cancer]. Interestingly, as compounds, the half-maximal inhibitory concentration [IC50] for these [CDK4/6 inhibitors] is not as you would expect in terms of OS. The best IC50—or the best way to inhibit the molecule—is with abemaciclib. The next is palbociclib, and ribociclib had the highest IC50, so that’s not a signal for us to decide why this [OS benefit] happened.

The other reason to choose one [agent] over another is due to toxicity. Palbociclib has been very easy to use, and maybe that is one of the reasons for future trials to use that medication in combination with other compounds. If the OS is not there, we could look at combinations because of the favorable toxicity profile.

Of the 2 drugs that did show an OS benefit, ribociclib and abemaciclib, ribociclib has a very similar [safety] profile to palbociclib, with some diarrhea and some liver function test elevations that can be managed, usually by dose reduction. Abemaciclib is given continuously with the prominent difference being less neutropenia and more diarrhea.

So which CDK4/6 inhibitor should you use in first-line metastatic breast cancer that's HR positive/HER2 negative? While we have a lack of head-to-head trials, an OS benefit has been seen in all ribociclib trials and abemaciclib trials, with a likely benefit in MONARCH 3. [There is] no OS benefit in PALOMA-2. PALOMA-3 is close to an OS benefit; however, it is not statistically significant, not reaching the prespecified end point, and the toxicity difference probably drives some of the [treatment] decisions.

Shifts in the Management of Metastatic HER2-Positive Breast Cancer

Shagisultanova: [In] HER2-positive [metastatic] breast cancer, we [saw multiple] new agents and updates from the 2022 SABCS. In particular, [we saw updates from] the phase 2 HER2CLIMB trial [NCT02614794], which was a pivotal trial that changed therapy for patients with brain metastases. [We also saw the] latest updates with fam-trastuzumab deruxtecan-nxki [Enhertu] presented from the phase 3 DESTINY-Breast02 [NCT03523585] and DESTINY-Breast03 [NCT03529110] trials.

I also touched base on the most recent trials in early HER2-positive breast cancer, including the phase 3 KATHERINE trial [(NCT01772472) of ado-trastuzumab emtansine (Kadcyla) vs trastuzumab (Herceptin) as adjuvant therapy] and the phase 3 FeDeriCa trial [(NCT03493854) of pertuzumab (Perjeta) and trastuzumab in combination with chemotherapy], both of which were practice-changing trials.

In the first line for metastatic breast cancer expressing HER2, we have the [regimen from the phase 3] CLEOPATRA trial [NCT00567190] of docetaxel combined with trastuzumab and pertuzumab. After 6 to 8 cycles of docetaxel, you can move these patients to maintenance therapy with trastuzumab and pertuzumab. [Additionally], if their tumors are ER [positive], you can add endocrine therapy. This is firmly the [standard] first-line therapy in HER2-positive metastatic disease.

A lot is going into [determining the optimal] second-line therapy. We have two competing regimens. One is the ‘new kid on the block,’ the drug that was a disruptor in the HER2 space, trastuzumab deruxtecan, which came out and changed everything with how we manage this cancer. We also have a regimen of capecitabine [Xeloda], trastuzumab, and tucatinib [Tukysa], which changed standard-of-care treatment for patients with brain metastases.

Case-Based Discussion of HER2-Positive Breast Cancer

Acharya-Leon: Looking at a clinical case, this is a patient with metastatic HER2-positive breast cancer who receives first-line therapy followed by maintenance therapy. She has episodes of headaches, and she has 3 new brain metastases [between] 4 to 6 mm. What [treatment] would you choose and why?

The first choice is radiate again and continue trastuzumab and pertuzumab, [then] switch to trastuzumab deruxtecan; radiate again and switch to trastuzumab deruxtecan; or use the HER2CLIMB regimen, which includes tucatinib. When we look at this, based on the data presented, we would choose the HER2CLIMB regimen.

Shagisultanova: I stressed in my presentation that [the HER2CLIMB] regimen was used in patients with untreated brain metastasis. We could send the patient to radiation again, but it is associated with a lot of discomfort, and patients with brain metastases tend to get repeated rounds of radiation. Whenever I can use an agent that [potentially spares] patients from radiation in the future, I would [favor that] regimen––in this case the [HER2CLIMB] regimen.

I tend to use a lot of tucatinib in patients with brain metastases. Interestingly, radiation oncologists are aware of [this regimen], and [they could suggest to] not radiate a patient and use tucatinib. We want to see the response to tucatinib before we decide [on radiation]. In many cases, we can avoid radiation and save it for the future. These patients tend to get repeated rounds of radiation, and they will have enough radiation later.

That is the reason in this case I would use the HER2CLIMB regimen. Otherwise, a perfectly good option would be to radiate again and switch to trastuzumab deruxtecan. However, tucatinib does not have a risk of pneumonitis. It's a perfect placement [of tucatinib] for patients with small, asymptomatic new brain lesions where you can avoid radiation and place them on a regimen, and their brain disease will be controlled for a long time.

The Continued Exploration of Sacituzumab Govitecan in Triple-Negative Breast Cancer (TNBC)

Diamond: The phase 3 ASCENT trial [NCT02574455] confirms the benefit of sacituzumab govitecan-hziy [Trodelvy] compared with single-agent chemotherapy with an improvement in OS, progression-free survival, and response rate. Neutropenia is common, and granulocyte colony stimulating factor [G-CSF] was administered in [approximately] 50% of patients. However, discontinuation because of adverse effects was uncommon. [ASCENT] led to the full approval of sacituzumab govitecan in metastatic TNBC.

There are lots of studies that are ongoing with sacituzumab govitecan. For example, we have the phase 3 SASCIA trial [NCT04595565] looking at this agent in the adjuvant [setting] for patients that got neoadjuvant chemotherapy and didn’t have a pathologic complete response. This study is being run by the German Breast Group, primarily in Europe, but we look forward to those results. Other studies [are evaluating sacituzumab govitecan] in combination with immunotherapy and in the frontline setting.

The Next Steps for Identifying Opportunities in HER2-Low Breast Cancer

Borges: HER2 low is a tremendous space of opportunity for these antibody-drug conjugate technologies. We will likely see additional drugs that have the same target but different linkers. I would say that I consider HER2 low a spectrum but not a unique biology. It's just a different level of HER2, but it is still the same pathway, [so this strategy] makes sense. However, trying to target HER2 with our other HER2[-targeted] drugs has not yet been shown to be effective, so we don’t want to think that if one thing works in HER2 low, other things will, too. These things need to be studied appropriately.

We don’t know how low we can go [with HER2 expression]. There are even ultra-low levels of cutoff, and we will see future studies getting into this. There were some beautiful topics delved into deeply by pathologists at the 2022 SABCS. We're going to have several years of papers and reviews in our major clinical trials, and we'll see where it goes.

We have been debating what the right level of ER [expression] is to consider treatment for decades. We've been debating the types of HER2 testing, what matters, and what benefits patients. Always make sure to follow the clinical trial and what got the patient onto the trial that allowed us to see the benefits.

What other things can we do that will move this field forward to where metastatic breast cancer will be something patients are living with for multiple decades, not just in the ER space or the high HER2 space? In this HER2-low group, we have the opportunity to move the field forward.

Classifying Risk Factors for Breast Cancer

Wood: Gene [mutations] such as BRCA1 or BRCA2 are not very common in the [breast cancer] patient population, but they confer a very high risk for cancer. Then we have what we term moderately penetrant gene [mutations], which include CHEK2 and ATM. PALB2 is probably a high-risk gene at this point. Finally, we have low-risk genes or a combination of genes.

It is important to realize that ductal carcinoma in situ [DCIS] and lobular carcinoma in situ [LCIS] are important risk factors for breast cancer and far outweigh a lot of other risk factors.

When we think about genetic risk factor, two back-to-back papers in The New England Journal of Medicine [in 2021] showed that BRCA1 is our highest risk gene. BRCA2 has a little bit of a lower risk. PALB2, as mentioned, is one of the higher-risk genes. CHEK2 and ATM are moderate-risk genes. Other risk genes [include] RAD51C, RAD51D, and BARD1.

What do we do about these risks? We do have some lifestyle modifications. Moderation is important. The same is true for exercise, weight maintenance, and breastfeeding. There are medications that we can offer our patients, and there are surgical options. There are both hormonal options and non-hormonal options.