Trastuzumab Deruxtecan Could Challenge Frontline Trastuzumab/Pertuzumab Combo in HER2+ Breast Cancer

The combination of trastuzumab (Herceptin), pertuzumab (Perjeta), and taxane remains the preferred frontline treatment of HER2-positive metastatic breast cancer. However, fam-trastuzumab deruxtecan-nxki [Enhertu] alone or in combination with pertuzumab could challenge that standard of care, according to Sara A. Hurvitz, MD.

“Those results [with trastuzumab, pertuzumab, and taxane] may be bested by the results of the ongoing [phase 3 DESTINY-Breast09] study [NCT04784715] looking at trastuzumab deruxtecan,” Hurvitz said. “However, until we have those results, taxane plus trastuzumab and pertuzumab is the standard regimen of choice in the frontline setting.”

In an interview with OncLive® following the State of the Science Summit™ on women’s health, Hurvitz discussed the evolving treatment paradigm in HER2-positive breast cancer, ongoing research in the space, and developments in the treatment of triple-negative breast cancer (TNBC). She is an associate professor at the David Geffen School of Medicine at University of California, Los Angeles (UCLA); medical director of the Jonsson Comprehensive Cancer Center Clinical Research Unit; co-director of the Santa Monica-UCLA Outpatient Oncology Practices; and director of the Breast Cancer Clinical Trials Program at UCLA.

OncLive^®: How has the targeted treatment landscape for HER2-positive breast cancer changed in recent years?

Hurvitz: In terms of HER2-positive breast cancer, there have been a stunning number of changes in the past 5 years due to the development of a variety of targeted agents for this disease.

We currently have 8 different HER2-targeted therapies available for patients diagnosed with HER2-positive advanced breast cancer, and outcomes appear to be improving over time, given the availability of these effective systemic therapies.

What progress has been seen in the second- and later-line settings?

In the second-line setting, our new standard is trastuzumab deruxtecan, an antibody-drug conjugate [ADC] that targets HER2 and has shown phenomenal results when compared against ado-trastuzumab emtansine [Kadcyla; T-DM1], making it the standard of care after a patient’s disease has progressed on trastuzumab and taxane.

In the third-line setting and beyond, we have a variety of agents, including [the combination of] tucatinib[Tukysa], capecitabine [Xeloda], and trastuzumab, based on the [phase 2] HER2CLIMB trial [NCT02614794]. Tucatinib is a HER2-selective TKI that has shown great activity when added to capecitabine and trastuzumab, and interestingly, it shows good activity in patients with brain metastases. This is our standard third-line approach.

After that, we have drugs such as trastuzumab emtansine, capecitabine, neratinib [Nerlynx], and margetuximab-cmkb [Margenza], as well as trastuzumab combined with chemotherapy. [We also have] a ton of therapies that target HER2 that are in development, including a number of HER2-directed bispecific antibodies, novel ADCs, immune-based therapies, and combination therapies in which a HER2-targeted agent is combined with a PI3K inhibitor, a CDK4/6 inhibitor, or other targeted inhibitors.

This field remains exciting and promising as more therapies are developed and tested in the clinical trial realm.

What developments in TNBC stand out to you?

Although this remains an area of unmet need given the aggressiveness of TNBC and the poor outcomes associated with this disease, we have seen some rays of hope in the past 5 years with the approval of the checkpoint inhibitor, pembrolizumab [Keytruda], in the frontline setting combined with chemotherapy, based on the [phase 3] KEYNOTE-355 trial [NCT02819518], for those patients whose tumors have a PD-L1 combined positive score [of at least 10].

Moreover, we have the availability of sacituzumab govitecan-hziy [Trodelvy], a TROP2-targeted ADC that can be used in the second-line setting and beyond, and it has been shown to be associated with improved progression-free survival and overall survival compared with single-agent chemotherapy. We have PARP inhibitors available for those patients with TNBC who have a germline BRCA1/2 mutation.

We also have a ton of clinical trials in this area looking at novel ADCs, targeting things such as LIV-1 or TROP2. We have other immune-based combinations being tested, as well as PI3K inhibitors being tested.

This is an area of active research with a ton of questions to be addressed. Hopefully in the next year or 2, as we update the data for advanced TNBC, we will begin to see that we are improving survival for our patients diagnosed with this type of breast cancer.

What ongoing research is taking place at the UCLA Jonsson Comprehensive Cancer Center?

We currently have 2 very exciting, investigator-sponsored trials. One is a study called the phase 2 TALENT trial [NCT04553770], in which patients with HER2-low, hormone receptor [HR]­–positive, early-stage breast cancer are enrolled and treated with trastuzumab deruxtecan either alone or with an aromatase inhibitor prior to surgery.

Tissue samples are being taken, blood [is being drawn] for biomarker research, and we are measuring the rate of pathologic complete response [pCR] to trastuzumab deruxtecan for patients with this disease subtype. It is an exciting study because for HR-positive, non–HER2-amplified breast cancer, the chance of obtaining a pCR is extremely low with our current therapies such as endocrine therapy and chemotherapy. Our hope is that using this HER2-targeted ADC, which has shown much benefit for patients with HER2-low disease in the advanced setting, will also show benefit in the neoadjuvant setting.

My colleague Nicholas P. McAndrew, MD, also has an investigator-sponsored trial looking at tucatinib combined with ribociclib [Kisqali] and trastuzumab in HER2-positive breast cancer. It is a neoadjuvant study that will open as soon as a dose-escalation study combining these agents for the first time is completed. That is another exciting trial that is ongoing at UCLA that is sure to bring a lot of attention once we have early results.