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Adam M. Brufsky, MD, PhD, FACP, discusses the rationale to evaluate HER2-directed bispecific antibodies in HER2-positive breast cancer, the emergence of zanidatamab as a potential treatment strategy, and the unmet medical need the agent could fill in this disease.
Armed with a unique mechanism of action, bispecific antibodies, such as zanidatamab, represent a novel class of agents that could have widespread clinical implications for patients with heavily pretreated HER2-positive breast cancer who, even with significant growth in the paradigm, are likely to develop progressive disease, said Adam M. Brufsky, MD, PhD, FACP.
“We [are] manipulating the HER2 receptor, which is central to the pathogenesis of HER2-positive metastatic breast cancer. We have a lot of [HER2-directed] agents now, but we are still going to have patients who progress beyond everything we have,” Brufsky said.
“These patients are going to need agents to move the survival of the disease beyond the 5 years that it is [now]. We hope to make the survival of this disease 10 years [or more]. Bispecific antibodies are an option that patients have, but we can potentially move that option forward if [zanidatamab] turns out to be successful,” said Brufsky, a professor of medicine at the University of Pittsburgh School of Medicine and associate division chief for the Division of Hematology/Oncology in the Department of Medicine.
During the 2021 San Antonio Breast Cancer Symposium, data from part 3 of the phase 1 ZWI-ZW25-101 trial (NCT02892123) were presented, demonstrating encouraging antitumor activity with the addition of zanidatamab to single-agent chemotherapy in heavily pretreated patients with HER2-positive breast cancer.1
At a median follow-up of 7.1 months and among 22 evaluable patients, zanidatamab plus chemotherapy yielded a confirmed objective response rate (ORR) of 36.4%. When paired with zanidatamab, the ORR was 27.3% with vinorelbine, 42.9% with capecitabine, and 50% with paclitaxel.
Additionally, the combination was associated with a clinical benefit rate (CBR) of 54.5%, a disease control rate of 86.4%, and a duration of response (DOR) ranging from 1.6 months to over 22.1 months. The median progression-free survival was 7.3 months.
In an interview with OncLive®, Brufsky, who is also the medical director of the Magee-Women’s Cancer Program of UPMC Hillman Cancer Center, associate director for clinical investigations at UPMC Hillman Cancer Center, and codirector of the Comprehensive Breast Cancer Center, discussed the rationale to evaluate HER2-directed bispecific antibodies in HER2-positive breast cancer, the emergence of zanidatamab as a potential treatment strategy, and the unmet medical need the agent could fill in this disease.
Brufsky: The idea behind anti-HER2 monoclonal antibodies in general is to interact with the HER2 receptor. There are multiple domains on the HER2 receptor. There is one that trastuzumab [Herceptin] binds to that blocks confirmational changes to the receptor and, therefore, inhibits downstream signaling. Pertuzumab [Perjeta] binds to another domain of the HER2 receptor and blocks its interaction with HER3. However, people have had a lot of other ideas with these monoclonal antibodies.
For example, we have a lot of antibody-drug conjugates, such as ado-trastuzumab emtansine [T-DM1; Kadcyla], [fam-]trastuzumab deruxtecan[-nxki; Enhertu], and SYD985, [all of which use HER2 for payloads. However, there is a whole idea beyond that where we are trying to use novel bispecific antibodies that bind to HER2 and other epitopes. There is an anti-HER2 antibody that binds to CD3, for example, which brings T cells into the extracellular space and, perhaps, improves the immune response. That is one idea of a bispecific antibody.
Zanidatamab is a very interesting antibody in that it binds to 2 separate epitope regions on the HER2 molecule. By doing that, it clusters the receptors together, which can inhibit cell growth and have more antibody-dependent cytotoxicity—that is immune-cell destruction—of the HER2-positive cells.
It’s interesting and it does meet an unmet medical need here in that we have nothing beyond [a certain point]. We have available agents potentially to the fourth-line setting with THP [paclitaxel, trastuzumab, and pertuzumab] chemotherapy, trastuzumab deruxtecan, or T-DM1 depending on [global location], tucatinib [Tukysa], and trastuzumab/capecitabine [Xeloda]. Whatever we didn’t use in the third-line setting, we’d use in the fourth line. We also have margetuximab[-cmkb; Margenza], which is an interesting antibody that has an engineered Fc fragment, which is the back end of the molecule that interacts with the immune system.
We have a lot of monoclonal antibody ideas out there, but the idea behind zanidatamab is to improve the clustering and movement of the various HER2 molecules on the cell surface. There are several phase 1/2 trials that have been ongoing. One study [evaluating zanidatamab] with various chemotherapies was presented during the 2021 SABCS. It was a phase 1 trial [that enrolled patients with] metastatic HER2-positive breast cancer. Patients would have had prior HER2-directed therapies with trastuzumab/pertuzumab and T-DM1, so [zanidatamab is being evaluated in] the third-line setting. Patients got zanidatamab with vinorelbine, capecitabine, or paclitaxel. The primary end point was safety.
Generally, the drugs were safe and there wasn’t much additional toxicity beyond the chemotherapy[-related toxicities]. In fact, the dose-limiting toxicity appeared to be neutropenia. Again, there was some pneumonitis, but it was found to be unrelated to the treatment itself.
There was a nice response rate to all the [combinations] in these pretreated patients. We saw a response rate of over 50% with zanidatamab and paclitaxel. However, the ORR to all chemotherapies was about 36%, the CBR was about 54%, and the DOR was anywhere from 1.5 months up to 22 months.
It’s interesting, and these drugs are being tried in multiple settings. We are very interested in seeing where this bispecific antibody with a novel mechanism of action will go.