Trastuzumab Deruxtecan Shakes Up Treatment Possibilities for HER2-Low Metastatic Breast Cancer

Katherine Tkaczuk, MD

The benefit displayed by fam-trastuzumab deruxtecan-nxki (Enhertu) vs physician’s choice of chemotherapy in the phase 3 DESTINY-Breast04 trial (NCT03734029) affirmed the classification of patients with HER2-low metastatic breast cancer as a separate subset. Based on data from DESTINY-Breast04, the FDA approved trastuzumab deruxtecan for the treatment of patients with unresectable or metastatic HER2-low breast cancer in August 2022.¹

“These patients, when treated with standard-of-care chemotherapies, don’t do well. Having another agent such as trastuzumab deruxtecan [is important] for this patient population,” Katherine Tkaczuk, MD, said in an interview with OncLive^® following an Institutional Perspectives in Cancer webinar on breast cancer.

In the interview, Tkaczuk, discussed practice-changing data across breast cancer subtypes that were discussed at the 2022 ASCO Annual Meeting, including data from DESTINY-Breast04 and the phase 3 PALOMA-2 trial (NCT01740427), plus the utilization of CDK4/6 inhibitors and PARP inhibitors for select patients with breast cancer. Tkaczuk is the director of the Breast Evaluation and Treatment Program at the University of Maryland School of Medicine Marlene and Stewart Greenebaum Cancer Center.

OncLive^®: How has the use of subcutaneous pertuzumab (Perjeta) and trastuzumab (Herceptin) helped improve quality of life for patients with HER2-positive breast cancer?

Tkaczuk: I had the pleasure of discussing the [phase 3] FeDeriCa trial [NCT03493854] and the Phesgo [subcutaneous pertuzumab, trastuzumab, and hyaluronidase-zzxf] data. This is a very interesting study that looked at pharmacologic equivalency of the subcutaneous formulation of trastuzumab and pertuzumab compared with intravenous [IV] formulations. Phesgo is now FDA approved for the treatment of [HER2-positive] breast cancer in the adjuvant, neoadjuvant, and metastatic settings.

In terms of [Phesgo’s] use, it is still underused. The FeDeriCa trial showed that this subcutaneous formulation is equivalent [to the IV formulation]. A majority of the patients in FeDeriCa and the [phase 2] PHranceSCa trial [NCT03674112] preferred the subcutaneous formulation. It is much easier for patients. They don’t have to stay in the infusion centers to receive IV trastuzumab and pertuzumab. [Regarding] quality of life, it is something to consider.

This is what we’re now switching to at the University of Maryland. A lot of our patients are being switched to the subcutaneous formulation of trastuzumab and pertuzumab.

Additionally, I discussed the [phase 3] KATHERINE trial [NCT01772472] in patients with HER2-positive breast cancer who have residual disease after neoadjuvant chemotherapy. In this trial, the antibody-drug conjugate [ADC] trastuzumab emtansine [T-DM1; Kadcyla] was compared with trastuzumab in the adjuvant setting. These data are not new, though there have been some additional updates. Currently, this is really the only approach for those patients who have residual disease after neoadjuvant chemotherapy, where patients should be recommended to receive their adjuvant therapy with T-DM1. This trial showed improved event-free survival [EFS] for patients treated with the ADC compared with trastuzumab.

What stood out about the efficacy data that was observed with trastuzumab deruxtecan in the phase 3 DESTINY-Breast03 trial for HER2-positive breast cancer?

DESTINY-Breast03 was a randomized trial looking at trastuzumab deruxtecan compared with T-DM1 in patients with HER2-positive, advanced breast cancer. Those data were already published, and there was a significant improvement in the [progression-free survival (PFS)] for treatment with trastuzumab deruxtecan. This treatment also significantly improved response rates compared with the control arm. This is in HER2-overexpressed or positive breast cancer, as we often refer to these patients. These patients must have had HER2 expression that is 3+ by immunohistochemistry [IHC] or fluorescence in situ hybridization positive.

What were the key findings that led to trastuzumab deruxtecan’s approval for HER2-low breast cancer?

The DESTINY-Breast04 trial looked at patients that would be considered HER2-low. In this trial, patients were either 1+ or 2+ expressors [of HER2 per IHC]. This trial showed a statistically significant improvement [in PFS and overall survival (OS)] when patients were treated with trastuzumab deruxtecan compared with [physician’s choice of chemotherapy].

In terms of the HER2-low patients, the results of the DESTINY-Breast04 trial showed a significant improvement in PFS in favor of trastuzumab deruxtecan compared with physician’s choice of chemotherapy. The difference was striking. We saw almost a doubling of the PFS from about 5.4 months to 10.1 months.

These interesting data represent new data in [the HER2-low] patient population. A majority of these patients in this trial were hormone receptor [HR]–positive and had been exposed to prior hormonal therapies, so they presumably had hormone resistance. These patients, when treated with standard-of-care chemotherapies, don’t do well. Having another agent such as trastuzumab deruxtecan [is important] for this patient population.

Paula Rosenblatt, MD, of the University of Maryland Marlene and Stewart Greenebaum Cancer Center, discussed the role of CDK4/6 inhibitors in estrogen receptor (ER)–positive breast cancer. How could these agents play a role in the adjuvant setting?

We currently have 3 CDK4/6 inhibitors in [ER-positive breast cancer]: palbociclib [Ibrance], ribociclib [Kisqali], and abemaciclib [Verzenio]. These are recommended in the first- or second-line setting, in combination with hormonal therapies, in advanced [ER-positive] metastatic breast cancer.

All these agents have shown improvement in PFS compared with hormonal therapies alone. In terms of OS benefit, we have data for a couple of these agents. At the 2022 ASCO Annual Meeting, [the final OS analysis from the PALOMA-2 trial] was presented, where the secondary end point of OS for this trial was not [statistically] significant. Previous publications from the [phase 3] MONALEESA-2 trial [NCT01958021] showed an OS benefit for the combination of ribociclib and hormonal therapy [vs hormonal therapy alone]. These agents, in terms of the delay in [disease] progression, remain excellent [options], and patients tolerate the combinations well.

At this time, in terms of the adjuvant space, the only data that we have to support adjuvant treatment with a CDK4/6 inhibitor comes from the [phase 3] monarchE trial [NCT03155997], where patients with high-risk, HR-positive, HER2-negative breast cancer were treated with abemaciclib in combination with adjuvant hormonal therapies.

The trial supports that approach in the adjuvant setting. But in the metastatic setting, the PFS benefit remains significant for all 3 CDK4/6 inhibitors. We have seen a significant improvement compared with hormonal therapy alone [in that setting]. This [approach] should remain the standard of care in the first- and second-line [metastatic] setting.

Aaron Iddings, MD, of the University of Maryland Marlene and Stewart Greenebaum Cancer Center, discussed the use of the PARP inhibitor olaparib (Lynparza) in the adjuvant setting for patients with high-risk, early-stage, BRCA1/2-mutated breast cancer. What factors contribute to the decision to use olaparib in this setting?

The FDA approval [for olaparib] based on findings from the [phase 3] OlympiA trial [NCT02032823], which met its primary end point of disease-free survival [DFS]. Olaparib was compared with placebo in this randomized trial. Patients had to have BRCA1/2 germline mutations. This trial was done in patients who had prior neoadjuvant or adjuvant therapy. Patients could have had either ER-positive or -negative disease. They had to be HER2-negative. For patients [with triple-negative breast cancer (TNBC)], the eligibility called for T2 disease, so higher-stage patients were included in this randomized trial.

For ER-positive patients, the eligibility criteria were set up so that only the higher-risk patients with over 4 positive lymph nodes in the adjuvant setting [were included]. There was an additional algorithm that selected higher-risk patients. Typically, if you use the algorithm that investigators used, you would select patients with higher-stage disease, more positive lymph nodes, or larger tumors post neoadjuvant chemotherapy.

Those patients with higher-risk, germline BRCA–positive cancers should be considered for adjuvant treatment with olaparib. It is important to mention that although both ER-positive and -negative patients had a benefit from the addition of olaparib in adjuvant setting, the trial included primarily ER-negative patients. But for subgroup analyses, patients with HR-positive/HER2-negative or TNBC derived benefit from this approach. The HR-positive patients represented a smaller number of patients in this trial.

Ghazal Kango, MD, of the University of Maryland Marlene and Stewart Greenebaum Cancer Center, further elaborated on the clinical implications of HER2-low. What did DESTINY-Breast04 mean for identifying patients with HER2-low breast cancer as a separate subset of patients?

The DESTINY-Breast04 trial is practice changing because prior knowledge on HER2-positive breast cancer goes back to the initial pivotal trials in the metastatic setting with trastuzumab, followed by additional trials in patients who were HER2-low, including the [phase 3] NSABP B-47/NRG trial [NCT01275677] that I was part of. This was a negative trial. It was an adjuvant trial in [patients with] HER2-low breast cancer to assess whether trastuzumab benefits patients with HER2-low breast cancer.

Eligibility included node-positive or high-risk, node-negative breast cancer. Patients were randomized to receive standard-of-care chemotherapy with or without trastuzumab for 1 year. This trial was negative both for invasive disease-free survival and OS. Until now, we had no evidence from clinical trials that anti-HER2 therapy was beneficial for patients who have HER2-low breast cancer.

The DESTINY-Breast04 trial specifically looked at patients with metastatic HER2-low breast cancer. Here in this large phase 3 trial, patients were randomized to treatment with trastuzumab deruxtecan or physician's choice of chemotherapy. In terms of eligibility, the trial allowed prior chemotherapy for metastatic disease. They also allowed patients to have at least 1 prior line of hormonal therapy. Patients with stable brain metastases were included, which is true for most of the DESTINY-Breast trials.

The primary end point was PFS in HR-positive patients. Investigators also looked at the secondary end points of OS and PFS for all patients included.

Often, these patients were treated with single-agent chemotherapy and didn’t have the greatest outcomes overall. Having this new and novel treatment in this space is exciting and is one of the most exciting abstracts from the 2022 ASCO Annual Meeting.

Are there any additional trials or research ongoing at your institution that you would like to highlight?

We were part of the single-arm trial called the Expanded Access Phesgo trial [NCT04395508], which was done during the COVID-19 pandemic. This allowed patients with HER2-positive, early advanced breast cancer to receive therapy with Phesgo at home. They received this not at the infusion center, but at home with the visiting nurse.

This was something new, and there was a poster presentation on this at the 2022 ASCO Annual Meeting. Investigators were able to show that this approach of at home administration was safe and preferred by patients. We are certainly trying to improve patients’ quality of life with this type of research, though this approach is not currently approved to be done at home.

At the University of Maryland, we are involved in many trials, but the idea of more targeted therapies, not only for HER2-positive breast cancer, but for other subtypes of breast cancer, is still on the forefront of research in breast medical oncology.

Reference

1. FDA approves first targeted therapy for HER2-low breast cancer. News release. FDA. August 5, 2022. Accessed August 14, 2022. https://bit.ly/3d4X2JQ