Novel Agents and Potential Breakthroughs in HER2+ Breast Cancer Treatment

Yara Abdou, MD

Novel agents and combinations are emerging as potential treatments in the field of HER2-positive breast cancer, particularly in regard to targeted therapies. Bispecific antibodies like zanidatamab (ZW25) and antibody-drug conjugates (ADCs) like RC48 and trastuzumab duocarmazine (SYD985) have shown impressive efficacy in heavily pretreated and early-stage settings.

Another trial, a first-in-human, phase 1 chimeric antigen receptor (CAR) macrophage study being performed at the University of North Carolina (UNC) is combining targeted therapies with immunotherapy, including CAR macrophages with pembrolizumab (Keytruda). Findings have already appeared promising showing a possible new immune-based treatment for patients with solid tumors. Another study utilizing monocytes as precursors to macrophages is anticipated to open at UNC for the treatment of patients with HER2-overexpressing solid tumors.

Additionally, studies exploring ADC and checkpoint inhibitor combinations, CDK4/6 inhibitors with anti-HER2 agents, and de-escalation approaches offer exciting possibilities for individualizing treatment and minimizing toxicity.

In the second part of an interview with Targeted OncologyTM, Yara Abdou, MD, medical oncologist at UNC in Chapel Hill, provided a deep dive into the evolving landscape of HER2-targeted therapy and its potential to revolutionize cancer treatment.

Targeted Oncology: Regarding the novel agents targeting HER2 downstream signaling pathways, which hold the most promise and in what patient populations?

Abdou: There are several HER2-targeting novel agents that are being developed. An example of that are the HER2-targeted bispecific antibodies. An example of a HER2-targeted bispecific antibody is zanidatamab. That is an antibody directed against 2 domains of HER2, binding 2 distinct sites on the HER2, resulting in increased antibody-binding receptor clustering and downregulation of the HER2 receptor. That has been studied in heavily pretreated HER2-positive disease. There is also more data in the first-line setting with docetaxel that has shown promising efficacy. There's also some encouraging data in the neoadjuvant setting that was presented from a pilot phase 2 at [the 2023 European Society of Medical Oncology Congress], showing decent [pathological complete response (pCR)] rates with neoadjuvant ZW25, so lots of exciting data there.

Breast Cancer - Female Anatomy - pain concept: © peterschreiber.media - stock.adobe.com

There are other novel HER2-directed ADC’s, such as RC48, and there are early studies showing safety and efficacy with this agent. There are other ADCs, such as trastuzumab duocarmazine, that is composed of the trastuzumab in conjugation with a DNA-alkylating agent. That was evaluated in TULIP [NCT03262935], showing improved progression-free survival compared with physicians' choice of therapy, so lots of novel agents there. Another novel trial is the phase 1, first-in-human CAR macrophage study for HER2-positive solid tumors that we are participating in here at UNC. This is an individualized immune therapy where the patient's own primary macrophages are engineered to display an anti-HER2 CAR. This CAR macrophage treatment has shown to reprogram the tumor microenvironment through increased T-cell activation, proliferation, [and] myeloid cell activation, generating long-term immunity beyond the antigen targeted by the CAR agent.

[We anticipate] opening another study, which is a first-in-human, phase 1 study, also evaluating HER2-positive solid tumors. These are utilizing monocytes as precursors to macrophages. There are potential benefits to this approach, including the ability to differentiate into proinflammatory clear macrophages, antitumor mechanism of actions, along with an ability to produce higher cell yield and a faster manufacturing process. The study is anticipated to open early next year at UNC and many other sites here in the [United States], so lots of exciting stuff in HER2-positive disease.

Clinical trials often explore combinations of targeted therapies and immunotherapies. Are there any promising combinations that you are watching closely?

That is definitely a great approach. Immunotherapy has revolutionized the treatment landscape of many types of cancers. But unfortunately, in breast cancer, we are lagging behind, particularly in HER2-positive breast cancer. The ways to modulate that tumor microenvironment to make immune therapy more effective is definitely encouraged. One way to do that is by combining immune therapies with other agents, such as targeted therapies. The HER2-directed CAR macrophage study has a subcohort where we are combining the CAR macrophage with pembrolizumab. We have treated a handful of patients showing safety with the combination, but there is still no data on efficacy.

Other trials are combining ADCs with immune checkpoint inhibitors, particularly [trastuzumab deruxtecan (T-DXd)] with pembrolizumab in patients with previously treated HER2 classic breast cancer and other studies looking at PD-L1 with pembrolizumab in a similar setting. A study is looking at atezolizumab [Tecentriq] with TDM-1. There are also studies looking at combining targeted agents such as CDK4/6 inhibitors with anti-HER2 agents. This is another mechanism that has shown a synergistic effect, particularly for hormone-positive or HER2-positive breast cancer. They recently published a study [NCT04293276] with dalpiciclib [SHR6390] and pyrotinib [SHR-1258]. That is a phase 2 study showing activity in patients with hormone-positive, HER2-positive breast cancer. That was a small study, but definitely encouraging to see chemotherapy-sparing regimens showing significant antitumor activity in the frontline setting for HER2-positive breast cancer.

Looking ahead, what do you think could lead to major breakthroughs in coming years?

Often when we see beneficial results for patients with a new compound, the next step is to move it to the early-stage in the adjuvant or neoadjuvant setting. The goal is to prevent metastatic disease in the first place. In the early-stage setting, I look forward to data from DESTINY-Breast05 [NCT04622319], which is a phase 3 study looking at T-DXd vs TDM-1 in patients with HER2-positive breast cancer who have residual disease after neoadjuvant therapy. Another study in a similar space is CompassHER2-pCR [NCT04266249], which is another phase 3 study, randomizing patients with residual disease to adjuvant TDM-1 alone, which is the standard-of-care, vs TDM-1 and tucatinib (Tukysa). This is especially important because TDM-1 has shown improved outcomes for patients with residual disease, but it does not really decrease the risk of [central nervous system (CNS)] recurrence, so brain metastases, which continues to be a challenge in HER2-positive breast cancer. We need better agents in the early adjuvant setting to decrease the risk of CNS metastasis down the line.

In this space, I am also excited about the de-escalation trials. Anti-HER2 agents work well and in some patients, less is more. It is especially important for the patients who are predicted to do well, such as patients who have a pathologic complete response to have some de-escalation in their treatments, and perhaps less toxicity with their therapies. There is CompassHER2-pCR and then and the Decrescendo [NCT04675827] trial looking at individualizing the adjuvant therapies based on pCR status after a de-escalated neoadjuvant course. There is an in-depth study which we are participating here at UNC in looking at hormone therapy plus anti-HER2 therapy without chemotherapy as an adjuvant therapy for patients with stage I or II-positive disease.

What are some ongoing challenges that still need to be addressed in the space?

Despite all the treatment advancements, metastatic HER2-positive breast cancer remains incurable. Patients are still unfortunately dying from this disease. There is still a big unmet need to improve outcomes for patients. One of our biggest challenges in this disease remains the brain metastases. Especially with improved systemic control, the incidence of brain metastases have been increasing. It is estimated that about 50% of patients who have HER2-positive metastatic breast cancer will develop brain metastases. While we are now more conscious of this and are improving our research efforts towards this cause, brain metastases continue to do poorly. We continue to focus our efforts into understanding the efficacy of these agents in the brain. One way of doing that is allowing patients with active brain metastases to enroll on our clinical trials.

In metastatic breast cancer, the key is understanding that it is not just the longevity of life that makes it precious. It is the quality-of-life. This is where precision medicine comes into play. These allow us to personalize and enhance our treatment strategies and prolong our patients lives, but also minimize their suffering and toxicity from the disease and the treatments. That is always important for us to keep in mind as physicians and researchers. Despite all these treatment advances, we continue to see an abysmal enrollment of minority women in clinical trials. As we develop our precision medicine approaches, it is important for us to improve representation of diverse patients in clinical trials and maximize our efforts towards inclusion and diversity and research.

Read part 1: HERE