Treatment Selection Becomes Complex Amid Growing Armamentarium in HER2+ Breast Cancer

The treatment landscape of early-stage and metastatic HER2-positive breast cancer has undergone significant growth within the past few years, said Nusayba Bagegni, MD, who spotlighted agents such as ado-trastuzumab emtansine (T-DM1; Kadcyla), fam-trastuzumab deruxtecan-nxki (Enhertu), and tucatinib (Tukysa) as practice-changing additions to the space. 

“A couple of decades ago, [HER2-positive disease] was one of the more aggressive phenotypes of breast cancer,” explained Bagegni. “Since the discovery of trastuzumab [Herceptin], we’ve had multiple HER2-directed therapies come down the pipeline. Patients are doing better and living longer with less metastatic recurrences. It’s really an exciting time to treat patients in the HER2-positive setting.” 

The availability of these agents has not only led to improved outcomes for patients but allowed for greater flexibility and personalized treatment in pretreated settings, explained Bagegni. 

In an interview with OncLive^® during the 2020 Institutional Perspectives in Cancer webinar on breast cancer, Bagegni, an assistant professor of medicine within the Division of Medical Oncology at Washington University School of Medicine and a medical oncologist at Siteman Cancer Center, discussed prominent data that have emerged in early-stage and metastatic HER2-positive breast cancer. 

OncLive^®: Why does it make sense to use T-DM1 in the adjuvant setting for patients with high-risk HER2-positive breast cancer? 

Bagegni: We know that achieving pathologic complete response [pCR] is an important end point for our neoadjuvant HER2-positive trials. pCR is a surrogate for long-term outcomes in patients with aggressive tumor subtypes. We also know that patients who do not achieve a pCR have a higher risk of metastatic recurrence. 

Therefore, patients in the KATHERINE trial who didn’t achieve a pCR with conventional neoadjuvant taxane, trastuzumab, and pertuzumab [Perjeta] were able to receive a therapy in the [adjuvant] setting that they could respond to. 

T-DM1 is a novel antibody-drug conjugate [ADC]. It was approved in the metastatic setting in 2013 for patients who had prior therapy with taxane and trastuzumab and still had a response. Despite that similar combination, bringing [T-DM1] into the adjuvant setting in patients who have residual disease makes a lot of sense and provides patients with a novel and well-tolerated agent. 

Longer-term data from the KATHERINE trial were presented during the 2019 San Antonio Breast Cancer Symposium (SABCS). What effects have those data had on practice?

The KATHERINE trial really was very exciting, and I believe practice changing. We always ask: Is this going to change practice on Monday morning? [The KATHERINE data] absolutely did. At the 3-year follow up, where the median follow-up time was about 40 to 41 months depending on the cohort, patients had a significant improvement in invasive disease-free survival [iDFS]. The iDFS rate was 83% in patients who received T-DM1 vs about 77% in patients who received trastuzumab alone. 

This is a great way of treating patients and improving their outcomes after having a less than optimal response to neoadjuvant therapy. 

Have any notable differences been observed with T-DM1 in the early-stage setting vs the metastatic setting?

We found that patients generally tolerated [T-DM1] well. No new safety signals were [observed]. Toxicity wise, we tended to see thrombocytopenia and neuropathy, but these were generally low grade and well [managed]. I believe there were 5 cardiac events [in the KATHERINE trial], which translates to a very low rate. 

One concern that I initially had was the potential for more radiation pneumonitis with T-DM1; however, the rates [of radiation pneumonitis] were still low at 1.5% in the T-DM1 group.

I am very confident in treating patients with T-DM1 who are going to undergo concurrent radiation. I don’t feel that we have seen any additional or new concerns compared with our use of T-DM1 in the metastatic setting. 

Could the use of T-DM1 as adjuvant therapy in patients with residual disease after neoadjuvant therapy affect the utility of the FDA-approved biosimilars for trastuzumab? 

We are still incorporating [biosimilars into practice] for patients who achieve a pCR. A large group of our patients, especially those who are estrogen receptor [ER]–/progesterone receptor [PR]–negative and HER2-positive, achieve a pCR and are ineligible for adjuvant T-DM1. I think there is still a role for biosimilars, and we are incorporating them into our practice. 

Much of that [decision] is [based on] insurance preferences, but it also brings in the new subcutaneous, fixed-dose combination of trastuzumab and pertuzumab with hyaluronidase. That is certainly going to continue to be an option for patients who do achieve a pCR and then go on to likely continue trastuzumab and pertuzumab in the adjuvant setting.

What benefits can the subcutaneous trastuzumab/pertuzumab combination provide to patients compared with the intravenous [IV] formulation?

It is important to keep in mind that our patients in the early-stage setting are coming in for a full year of therapy. I [discuss giving] neoadjuvant or adjuvant therapy, followed by chemotherapy, followed by trastuzumab plus or minus pertuzumab for a year [with my patients]. That is a long time [to be on therapy].

[Treatment] is given every 3 weeks, so [patients are required] to come into the chemotherapy-infusion site, wait for labs to review prior parameters, receive the infusion, and then come back 3 weeks later. [This course of therapy] does have a place. Some of my patients feel very comfortable with the IV infusion, so there has been some hesitancy in discussing the subcutaneous formulation, which is an injection given in the upper thigh. Some patients feel uneasy about that. However, other patients have found it to be something that they certainly want to consider, especially after they complete their chemotherapy. 

The other important [factor] has been the coronavirus disease 2019 pandemic. Trying to minimize [patients’] exposure to the health care system [has been necessary]. If a patient doesn’t need to be [at the infusion center or hospital] for 30 or 60 minutes, and they can instead get [treatment] in 5 to 8 minutes. We can get patients in and out quickly [and] treat more patients [effectively].

Updated data from the APT and APHINITY trials have also been reported. How do those data inform clinical decisions in the early-stage setting? 

The 7-year [update] of the APT trial showed really excellent outcomes for patients. Specifically, an overall survival [(OS) rate] well above 90% and a DFS [rate] around 93%. Four patients had distant recurrence; patients did very well with the combination. That regimen has become a standard of care for patients with stage I or II HER2-positive breast cancer. 

With regard to the APHINITY trial, the 6-year follow-up data were presented during [the 2019] SABCS. That trial investigated the addition of pertuzumab to trastuzumab vs trastuzumab alone in patients with early-stage breast cancer who received adjuvant chemotherapy plus anti–HER2-based therapy. 

We found that patients who had lymph node–positive breast cancer seemed to benefit the most from the addition [of pertuzumab]. With the earlier analysis, we found that patients who [derived] more of the benefit initially were patients who had ER- or PR-negative disease, but we didn’t see that with longer-term follow-up. The benefit [in the longer-term follow up] was seen in patients who had lymph node–positive disease; those patients had a 4.5% improvement [in DFS], and patients benefitted regardless of ER or PR status. 

Could ADCs or other novel therapies replace the chemotherapy backbone in some of these regimens as a means to spare patients chemotherapy-related toxicities? 

Absolutely. I feel that there is a role for using ADCs. A number of trials are looking at T-DM1 in the neoadjuvant setting either alone or in combination with other anti–HER2-based therapies, such as pertuzumab. We have to choose the right patient population, specifically with regard to HER2 expression level. We have more information looking at HER2 heterogeneity and the role of HER2-targeted therapies. Some patients have great responses and less toxicity [with those options].

Currently, the standard of care is chemotherapy plus dual anti–HER2-based therapy, but that comes with a lot of toxicity. These can be difficult regimens to endure. Some patients may not be candidates for that type of therapy and the [regimen may be too toxic for] patients who are candidates. To potentially spare some patients [that toxicity], coming up with novel strategies, such as utilizing ADCs, and [developing] new management strategies are important. 

An [ongoing] trial is looking at T-DM1 plus or minus tucatinib in the adjuvant setting in patients who don’t achieve a pCR [with neoadjuvant therapy]. It is kind of a KATHERINE-like trial, but in combination with tucatinib or placebo. We certainly look forward to [those results].

Does the variability of HER2 expression affect treatment selection?

At present, we don’t have the clinical means of utilizing HER2-low expression outside of a clinical trial. There is certainly a role [for HER2-low expression] in clinical trials. [This is specific to those that are evaluating] new ADCs, such as trastuzumab deruxtecan.

However, at present, [it’s not] standard of care to consider anti–HER2-based therapies in patients who are considered HER2-low outside of a clinical trial. Generally, we would use our routine standard definitions for HER2 positivity by fluorescence in situ hybridization amplification or HER2 with immunohistochemistry of 3+. 

Moving to the metastatic setting, trastuzumab deruxtecan has been an important addition to the armamentarium. Could you discuss the significance of the DESTINY-Breast01 data?

DESTINY-Breast01 trial allowed us to investigate the role of the novel ADC, trastuzumab deruxtecan. [The study] incorporated trastuzumab plus a linker to a cytotoxic and very potent payload of a topoisomerase 1 inhibitor. The drug-to-antibody ratio was higher than our other HER2-based ADC at 8:1. 

The initial [DS8201-A-J101] trial, and later the DESTINY-Breast01 trial, found remarkable utility with trastuzumab deruxtecan in very heavily pretreated patients with advanced HER2-positive breast cancer. In the trial, patients were treated with trastuzumab deruxtecan every 3 weeks until progression or [unacceptable] toxicity. We found an overall response rate of 60.9%, which is quite remarkable in patients who had a median of 6 prior lines of therapy. Also, 6% of patients achieved a complete response, and about 55% of patients achieved a partial response. Those responses were durable, with a median duration of response of nearly 15 months. 

None of us will forget the waterfall plot [from the DESTINY-Breast01 trial]; the majority of patients [derived] an excellent response. Obviously, we have to keep the toxicity profile in mind, particularly with regard to the [risk of] interstitial lung disease [ILD] or pneumonitis, which can happen at any point during treatment. I do follow patients [receiving trastuzumab deruxtecan] very closely to make sure they are aware of [ILD as a] potential adverse effect, as well as potential symptoms of ILD, so they can be mindful to notify us immediately [if they experience any of these symptoms].

Is ILD the Achilles heel of trastuzumab deruxtecan, or could further modification of this agent alleviate the risk of ILD?

We certainly need more information. Many ongoing trials are investigating [trastuzumab deruxtecan] in multiple settings, such as advanced HER2-positive, HER2-low, and gastric cancers. I’m hoping that more data [evaluating] the utility of this drug will shed light on the patients who are at a higher risk of developing [ILD] and any associated risk factors. 

How are you selecting between trastuzumab deruxtecan or the tucatinib-based triplet regimen that was evaluated in the HER2CLIMB study? 

At this point, after taxane, trastuzumab, and pertuzumab in the first-line setting, and T-DM1 in the second-line setting, we don’t have an established third-line option in the metastatic setting. We are trying to figure out how to sequence our new therapies.

We have the approved HER2CLIMB regimen of tucatinib plus capecitabine [Xeloda] and trastuzumab, as well as trastuzumab deruxtecan. How do we select the proper therapy for the right patient? 

A number of factors will have to be taken into account, including patient preference. [Tucatinib/trastuzumab/capecitabine] is a predominantly oral regimen vs [trastuzumab deruxtecan], which is an IV regimen. Patient’s disease burden and whether we need to achieve a quick response [are factors to consider. [If a patient requires a rapid response], I may consider using trastuzumab deruxtecan because the median time to response was less than 2 months. We also saw a rapid median time to response with the tucatinib combination. 

I may consider [tucatinib] in patients who have central nervous system metastases, particularly [in those] with active or progressing metastases who are otherwise doing well. Also, considering the OS advantage of the HER2CLIMB regimen [is necessary]. We don’t currently have the data to tell us what the most appropriate third-line option is. So, [third-line treatment decisions] come down to discussions between oncologists and patients, taking into account patient factors and disease factors. 

Looking to the future, have any investigational agents or approaches piqued your interest?

What is really interesting is the use of trastuzumab deruxtecan in HER2-low tumors. This is going to potentially expand [the agent’s use] to a larger group of patients and provide other patients the ability to have access to a drug that may ultimately help them. We have some preliminary data looking at [patients with HER2-low disease] and the response rate was 44%. Utilizing some of these drugs in other settings within breast cancer is really exciting. 

Also, combining CDK4/6 inhibitors with some of our anti–HER2-based therapies [is exciting]. We have the data from the monarcHER trial that read out recently. Bringing in novel combinations to the HER2[-negative] setting is going to be quite intriguing.