O’Regan Highlights Advances in Management of Metastatic Breast Cancer Across Subtypes

October 13 is Metastatic Breast Cancer Awareness Day, and the metastatic breast cancer treatment landscape has changed greatly in the past year.

New agents have been introduced into the treatment paradigm across breast cancer subtypes over the past few years, expanding options for patients and prolonging survival for those with metastatic disease, according to Ruth O’Regan, MD.

Treatments now can be individualized to a patient’s specific breast cancer subtype as well as to potential genetic drivers of their disease.

O'Regan is the chair of medicine and Charles A. Dewey Professor at the University of Rochester in New York, physician-in-chief at Strong Memorial Hospital, and an associate director of education and mentoring at the Wilmot Cancer Institute. She also served on the Advisory Committee for the Association of Community Cancer Centers Metastatic Breast Cancer Project.

In an interview with Targeted Oncology for Metastatic Breast Cancer Awareness Day, O’Regan discussed how the metastatic breast cancer landscape has changed with these approvals and suggested potential regimens that could further that change.

Targeted Oncology: How has the metastatic breast cancer landscape evolved in recent years?

O’Regan: Unfortunately, metastatic breast cancer, regardless of what subtype it is, is still considered incurable. However, some of the newer agents that we’ve used, the targeted agents that we have available, have actually prolonged survival for patients with metastatic disease while maintaining quality of life and also delaying the length of time [until they require] chemotherapy. The goals of treatment for a patient with metastatic breast cancer are to maintain quality of life and prolong survival.

As far as what’s evolved over the past several years, I think we’re getting a better understanding of different subtypes of breast cancer. The treatment for metastatic breast cancer is dependent on the expression of estrogen receptor [ER], progesterone receptor [PR], and HER2. And we thankfully have a lot of new agents in this area that are specific for a given subtypes of breast cancer.

Taking them one by one: for ER-positive metastatic breast cancer, the CDK4/6 inhibitors were game changers. They doubled the time of disease control in patients in the first-line setting and are also highly effective in the second-line setting. They really have become standard of care.

We actually had 4 different agents approved for metastatic HER2-positive breast cancer last year. And a lot of these are either tyrosine kinase inhibitors [TKIs]—these are pills that target the intracellular domain of HER2—and then, very excitingly, antibody-drug conjugates [ADCs] that deliver chemotherapy directly into HER2-positive breast cancer cells, and some new antibodies as well.

Even prior to last year, the median survival for a patient with HER2-positive metastatic breast cancer was in the range of 5 years. Now with these new agents, we hope it will be longer. And I think that’s the area where we’re seeing patients living with metastatic breast cancer for many years.

The last one is triple-negative breast cancer [TNBC], which has been much harder to treat for a number of reasons. First of all, we don’t really have any driving genes or proteins in TNBC. So historically, the treatment has been chemotherapy. That said, there have been some positive trials using immunotherapy in TNBC. Although that’s somewhat of a controversial area. For example, [there is] atezolizumab [Tecentriq], which was one of the checkpoint inhibitors approved for metastatic TNBC. But because its impact on survival wasn’t as great as we initially thought, Roche withdrew the FDA-approval.

TNBC is a very tough disease to treat because it’s really made up of a number of different subtypes, all of which require slightly different approaches. One area that I think is encouraging in TNBC, and in HER2-negative breast cancer in general, is the use of PARP inhibitors in patients who have BRCA1 and BRCA2 mutations. And, more recently, we’ve actually seen activity of these drugs in patients with other germline mutations, such as PALB2. So that will be another kind of targeted therapy specifically for patients who have these germline mutations.

Across all cancers, one of the things that we’ve seen over the past several years is the ability to do next-generation sequencing [NGS] on tumors. And that can sometimes—unfortunately not as much as we would like—provide targets in these cancers that we can treat therapeutically. So, along with that, in hormone receptor [HR]–positive breast cancer, [approximately] 40% have mutations in PI3 kinase. And we now have a drug called alpelisib [Piqray] that is effective in these PI3K-mutated cancers.

I think we’ll see more targets being identified [with] NGS [for which] we can use therapies. In HR-positive breast cancers, some of them develop acquired mutations in HER2, and we know that some of the HER2 therapies that we use, such as neratinib [Nerlynx], appear to be effective in these cancers, even though they’re actually not HER2-positive, but are HER2-mutated.

I think it’s a very exciting time. The number of new agents that are being approved is really quite astonishing. And I think we’ll see more approved as we get a better understanding of the genomic landscape of these metastatic cancers.

What do you feel were the most practice-changing trials from the past year?

In the HR-positive setting, what we’ve seen are survival data from some of the first-line CDK inhibitor trials, which I think confirmed the activity of these agents that we knew were there before. The SOLAR-1 trial [NCT02437318] [supported] the approval of alpelisib.¹ Obviously, that was practice-changing because it provided a second-line therapy for [approximately] 40% of patients with HR-positive breast cancer.

Certainly, an area that has been very productive in terms of clinical trials is the HER2-positive setting. We had the approval of tucatinib [Tukysa], a TKI that targets HER2, based on results of the HER2CLIMB study [NCT02614794].² This drug in particular appears to be effective in patients with brain metastases. It’s been used in the second- and third-line settings for HER2-positive breast cancer. The DESTINY-Breast01 study [NCT03248492],³ which looked at trastuzumab deruxtecan [Enhertu], which is an ADC that targets HER2, also showed very impressive results, showing that the majority of patients got a dramatic benefit from this agent, so that was approved. The one thing we have to watch out for with that agent is interstitial lung disease, which is rare but can be very serious in these patients. The NALA study [NCT01808573]⁴ led to the approval of neratinib, another TKI that was already approved in the early-stage extended adjuvant setting. And that is also an option for patients.

During ESMO [the European Society of Medical Oncology Congress 2021] we heard about the DESTINY-Breast03 study [NCT03529110]⁵ that compared T-DM1 [trastuzumab emtansine; Kadcyla], which is another ADC, with trastuzumab deruxtecan. The results of that are really quite remarkable as well, showing a very marked improved outcome with trastuzumab deruxtecan.

And then lastly, the SOPHIA study [NCT02492711]⁶ led to the approval of margetuximab [Margenza], which is a trastuzumab [Herceptin]-like antibody engineered in a slightly different way. That shows some modest benefit over trastuzumab in the third-line or later setting. So in the HER2-positive setting, there are a lot of trials going on [with] very exciting results.

We have a number of studies looking at immune checkpoint inhibitors. A KEYNOTE study looked at pembrolizumab [Keytruda], and the IMpassion trials looked at atezolizumab. Although the trials are positive for patients with PD-L1–positive disease or immune-driven cancers, the impact on survival is a little less clear. And for atezolizumab, the improved survival decreased over time to some degree, but there was a negative study with paclitaxel, and that’s one of the reasons [the indication was withdrawn]. So [there is] quite a bit of work to do in TNBC.

The other agent that’s very exciting in TNBC is sacituzumab govitecan [Trodelvy]. That was evaluated in the ASCENT study [NCT02574455],⁷ and it showed very striking activity compared with standard-of-care chemotherapy. That is approved in the third-line and beyond setting for TNBC. But I think a lot of us are using it in the second-line setting.

Trastuzumab deruxtecan, although it’s a HER2-directed agent, actually has activity in HER2-negative breast cancer as well. We may see some more data for patients with HER2-low cancers with trastuzumab deruxtecan.

What is the newest target being investigated in the metastatic space?

I think there are a lot of different targets being looked at. For example, in both triple-negative and HR-positive breast cancer, there are a number of agents out there that are being looked at targeting AKT. In the triple-negative setting, one of [the subtypes] is androgen receptor–positive. When we discovered this, it was very exciting because we have a lot of prostate cancer drugs that target the androgen receptor. Unfortunately, so far, the activity of these as single agents has been fairly modest. However, there are some data suggesting that CDK4/6 inhibitors or PI3 kinase inhibitors can enhance the activity of these antiandrogens. That’s definitely a viable target in TNBC.

But I think, overall, the problem with all of these agents is that they work, then they stop working. And I think one of the things that we’re really focused on is trying to work out what changes in the cancer when it becomes resistant to these agents and what new targets develop.

As I mentioned earlier, in the HR-positive setting, particularly for lobular cancers, this idea that you can acquire a HER2 mutation is very exciting. It really opens up the door for a whole bunch of new agents to be used in that subtype of breast cancer. And I have no doubt that we’ll discover a bunch of other new targets as well through NGS, but they’re the ones that appear to be most viable at this time.

What are your preferred first-line and later-line treatments for this setting?

For HR-positive disease, the standard, and this is what I use, is a combination of endocrine therapy and either an aromatase inhibitor or fulvestrant [Faslodex] with a CDK inhibitor. In the second-line setting, it really depends on whether the cancer has a PI3K mutation. If it does, we tend to use alpelisib. If it doesn’t, I would use everolimus [Afinitor] or just go to chemotherapy. Obviously, clinical trials are clearly something that we would always look at. For HER2-positive breast cancer, the first-line [standard] is the CLEOPATRA [NCT00567190] regimen, which is a taxane with pertuzumab [Perjeta] and trastuzumab.

Second line right now is T-DM1, but that could change [with] the results of the DESTINY-Breast03 study. In the second-line setting for patients with brain metastases, I think a lot of us use tucatinib.

And then third line, [it’s] whatever you haven’t used before. If you haven’t used trastuzumab deruxtecan, you would use that. If you haven’t used tucatinib, you would choose that, and then neratinib is also an option, as is margetuximab.

For TNBC, if the cancer is PD-L1 positive or has a high CPS [combined positive score], I think based on what we have right now, a lot of us are going to use pembrolizumab with either taxane or gemcitabine and carboplatin, given that atezolizumab is not available anymore. If they are not PD-L1 positive or have a high CPS, single-agent chemotherapy is typically what we do. Capecitabine and taxane would probably be something that we will consider.

And then in the second-line setting, depending on what you’re using the first time, usually a single-agent chemotherapy would be what we would use, including eribulin [Halaven]. But I think, based on the ASCENT study, a lot of us would use sacituzumab in the second-line setting for now, and if we don’t, we certainly use it in the third line.

For HR-positive breast cancer, there’s a lot of interest in oral selective ER down regulators, of which there are a number in clinical trials right now. They’re being looked at as single agents and have been looked at with CDK inhibitors. It is possible that one of those might get FDA approval in 2022 or 2023. They’re an exciting group of agents and are certainly going to be preferred over fulvestrant because they are oral, and that allows more sustained inhibition of the ER and PR compared with fulvestrant. So that’s a group of drugs that is quite interesting. And I think we’ll definitely see more about those as well.

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