Novel Adjuvant Strategies Reshape HER2+ Breast Cancer Treatment

Paolo Tarantino, MD

Following the publication of the KATHERINE trial (NCT01772472), a number of novel clinical trials have emerged with the use of antibody-drug conjugates (ADCs), checkpoint inhibitors, and TKIs aimed at further improving outcomes for patients with high-risk, early-stage HER2-positive breast cancer, according to Paolo Tarantino, MD.

In the second part of an interview with OncLive®, Tarantino discussed the effect of the KATHERINE trial on post-surgical treatment decisions, the rationale behind ongoing trials evaluating novel agents such as fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), tucatinib (Tukysa), and atezolizumab (Tecentriq) in the adjuvant setting, and the importance of clinical and molecular risk stratification in early-stage HER2-positive disease. He also addressed challenges in the metastatic setting following progression on T-DXd and underscored the need for real-world data and prospective trials to guide therapy selection.

Tarantino is a breast medical oncologist at Dana-Farber Cancer Institute in Boston, Massachusetts, and a researcher at the University of Milan in Italy.

OncLive: The KATHERINE trial demonstrated a significant overall survival (OS) benefit with adjuvant T-DM1 vs trastuzumab (Herceptin) in patients with residual HER2-positive breast cancer after neoadjuvant therapy. How has this influenced your post-surgical treatment algorithm?

Tarantino: I think the major change that occurred after the first presentation and publication of KATHERINE [was] that it suddenly became mandatory for all patients with stage II/III HER2-positive breast cancer to receive neoadjuvant treatment, because it showed that if you select those patients that have more aggressive and resistant disease and you escalate their treatment after surgery [that] can affect outcomes later.

We discovered that we can also impact OS. That was the biggest shift in HER2-positive breast cancer, which is a parallel shift to what has occurred in triple-negative breast cancer.

[Similarly], we try to always give neoadjuvant treatment before surgery and the trial showed that we can kind of revert the adverse prognostic effect of residual disease if we escalate and give better treatment after surgery. This [way of thinking] opened the way to new treatment strategies.

Besides showing that T-DM1 can improve OS in the adjuvant setting, we started thinking whether we could [improve outcomes even further] if we used an even better ADC in this setting. This [paved] the way for the design of the phase 3 DESTINY-Breast05 trial [NCT04622319], which is comparing T-DXd with T-DM1 in the adjuvant setting.

Additionally, in the KATHERINE trial, we still saw several patients having brain recurrence despite [treatment with] TDM-1. [So, another] idea was whether we could combine a modern generation TKI with T-DM1? This led to the phase 3 CompassHER2 RD trial [NCT04457596], which is combining T-DM1 with tucatinib in the adjuvant setting.

Some investigators [have also] thought of adding immunotherapy in the adjuvant setting, [and that idea will be evaluated in] the phase 3 ASTEFANIA trial [NCT04873362] with atezolizumab plus T-DM1.

In general, the idea is that we can rescue some of these patients that have high-risk disease that is resistant to neoadjuvant treatment with better adjuvant treatment. T-DM1 is the current standard, but we know that we can make it even better, either with a better ADC or with good combinations with T-DM1.

How do you define high clinical risk in early-stage HER2-positive disease, and how does this classification affect treatment intensity and choice of neoadjuvant regimens?

There are some pillars of oncology that have remained constant over time, and in 2025 the Tumor, Nodes, Metastasis [TNM] staging system [continues to be one of the most critical].

In the early stage, knowing how large the tumor is and how many lymph nodes are involved remains critical. For small tumors that are node negative, we know that most of these tumors, when they’re HER2 positive, [can be cured]. We can cure more than 90% of them with adequate treatment, but for tumors that are large and with several positive lymph nodes, we know that despite the best treatments we have, even if you achieve pathologic complete response, you can still have a higher risk of recurring so clinical factors such as TNM remain critical.

Another very important factor is how addicted to HER2 the tumor is. We know that tumors that have high HER2 expression tend to respond better to HER2-directed treatment. We also know that the immunologic profile of the disease is important, although we still don’t know how to implement that in clinical decision-making well enough. There is an assay that has been shown to be very promising.

Recently, [investigators] tried to put this all together, the TNM stage, the proliferation aspects of the disease, luminal differentiation, HER2 status, immunogenic factors, etc., into an assay called HER2DX that looks at 27 genes within the disease and tell [us] whether the disease is high or low risk.

This has not been validated prospectively, only in retrospective studies. However, we expect that some data from the phase 2 CompassHER2-pCR trial [NCT04266249] will be presented with HER2DX. This [assay] was added into the trial prospectively, and so it will be very important to look at this data, because in the future, maybe we’ll have a test similar to Oncotype DX in HER2-negative disease that will tell us [about] risk profiles. For the moment, the pillar remains the size of the tumor and the lymph node involvement.

What are your thoughts on incorporating novel agents, such as tucatinib or eribulin-based combinations into treatment after progression on trastuzumab deruxtecan in the metastatic setting?

The setting of patients after progression [on] T-DXd remains challenging, mostly because we don’t have great data. Right now, we don’t have any prospective trials with T-DXd-pretreated patients. We have to rely on retrospective studies, which suggest that, in general, you can still achieve a relatively decent PFS with treatment after progression on T-DXd.

It has been shown that with tucatinib, trastuzumab, and capecitabine, the median PFS after T-DXd is approximately five months, which is not outstanding, but it’s something. Also, with traditional chemotherapy, like eribulin or other chemotherapies, we also have seen somewhere around four to five months [for PFS]. We want [better for our patients], and this is why we are trying to develop trials in this space. For instance, we have an ongoing, investigator-initiated trial looking at sacituzumab govitecan-hziy [Trodelvy] with trastuzumab [Herceptin] after T-DXd. There’s [also] another trial testing microtubule ADCs after T-DXd, which is also an appealing treatment strategy.

Overall, I think it’s important to remember that we need to fill this gap, to develop clinical trials in patients that have progressed on T-DXd. Most of the patients that we see in the clinic nowadays with HER2-positive metastatic breast cancer will have received T-DXd, so it’s an important question to try to address. For the time being, it’s also important to produce real-world data. This is why at [the 2024] San Antonio [Breast Cancer Symposium], we presented an analysis from the Flatiron [database] that we hope to have published this year, showing the efficacy of different treatment regimens. Some data have also been produced by our Japanese and French colleagues showing some promising regimens after progression on T-DXd.

It’s important to further produce real-world data that can fill the gap while we wait for prospective evidence, which remains the most important. I do hope that we can try to develop effective regimens prospectively tested after T-DXd and we can try to develop better sequencing strategies for these patients instead of just relying on real-world data and gut feeling.

The one drug that really has revolutionized the way we treat patients with HER2-positive breast cancer is T-DXd, which showed outstanding results in the phase 3 DESTINY-Breast03 trial [NCT03529110], and has since become the standard [of care] in the second line. [Soon] we expect data from the phase 3 DESTINY-Breast09 trial [NCT04784715], which may take T-DXd to the first-line metastatic setting. There’s also DESTINY-Breast05 and DESTINY-Breast11 [NCT05113251] that may take the drug to the early setting.

One challenge with [T-DXd] is the risk of interstitial lung disease. We know that about 10% to 15% of the patients receiving T-DXd can develop this lung inflammation. It’s extremely important to raise awareness, to monitor patients closely with CT scans, and to give patients steroids in case they develop any-grade interstitial lung disease, because if identified and treated, [this] is reversible, and we can avoid escalation of severe cases.

We’re going to use this drug more and more. It’s an extremely active drug, but it does come with this challenging [adverse] effect [profile], so we really want patients to be able to benefit from this drug in the safest possible way.