Alberto Montero, MD, MBA, CPHQ, is a clinical director of the Breast Cancer Program at University Hospitals, medical director of the Clinical Trials Unit at Seidman Cancer Center, and professor of Medicine at Case Western Reserve University, all in Cleveland, Ohio. 

Alberto Montero, MD, MBA, CPHQ, explains the rationale for evaluating zanidatamab plus evorpacept in HER2-expressing metastatic breast cancer.

Dr Montero on the Rationale for Evaluating Zanidatamab/Evorpacept in HER2+ Metastatic Breast Cancer

“Evorpacept augments the effect [of antibody-dependent phagocytosis] because it's an anti-CD47 small molecule; [therefore], it increases the ability of the antibody-dependent phagocytosis.”

Alberto Montero, MD, MBA, CPHQ, clinical director of the Breast Cancer Program at University Hospitals, medical director of the Clinical Trials Unit at Seidman Cancer Center, and professor of Medicine at Case Western Reserve University, explains the rationale for evaluating zanidatamab-hrii (Ziihera) plus evorpacept in patients with HER2-positive and HER2-low metastatic breast cancer.

Zanidatamab is a bispecific monoclonal antibody that is directed against HER2, similar to trastuzumab (Herceptin) and other HER2-targeted antibodies, Montero begins. He explains that zanidatamab has an essential mechanism of action through an immune-mediated effect via antibody-dependent phagocytosis.

Therefore, combining zanidatamab with evorpacept increases the effect of antibody-dependent phagocytosis, as evorpacept is an anti-CD47 small molecule, he continues. This rationale supported the evaluation of the combination in a phase 1b/2 study (NCT05027139).

 the agent with evorpacept in patients with HER2-positive and HER2-low metastatic breast cancer. Early data revealed that patients in cohort 1 (n = 21) with HER2-positive metastatic breast cancer experienced a confirmed overall response rate (ORR) of 33.3% (95% CI, 14.6%-57.0%), which were all partial responses. Of note, the disease control rate was 71.4% (95% CI, 47.8%-88.7%), the median progression-free survival (PFS) was 3.6 months (95% CI, 1.8-11.0), and the median duration of response was not evaluable (range, 3.6-25.9). Among patients from cohort 2 (n = 15) with HER2-low metastatic breast cancer, the confirmed ORR was 20.0% (95% CI, 4.3%-48.1%), and the median PFS was 1.9 months (95% CI, 1.6-3.9).

The study included patients with locally advanced inoperable and/or metastatic HER2-expressing breast cancer identified by local or central laboratory test results, disease progression during or following the most recent regimen of systemic therapy for advanced cancer, measurable disease per RECIST 1.1 criteria, adequate organ function, and an ECOG performance status of 0 or 1.

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Dr Montero on Unmet Treatment Needs for HER2+ Metastatic Breast Cancer

“We need newer treatments that are more effective, particularly for when one of the currently approved HER2-targeted drugs stops working.”

Alberto Montero, MD, MBA, CPHQ, clinical director, Breast Cancer Medical Oncology Program, University Hospitals Seidman Cancer Center; associate professor, medicine, Case Western Reserve University School of Medicine, 

 for patients with HER2-positive metastatic breast cancer.

Chemotherapy is a hallmark of the current HER2-positive metastatic breast cancer treatment paradigm, which lacks agents that are not associated with significant toxicities, Montero says. Furthermore, although patients with this disease have several treatment options, the disease is incurable, according to Montero. Future research should focus on developing novel therapies that are effective for patients whose disease has progressed on prior lines of HER2-targeted therapy, he emphasizes.

, Montero and colleagues presented data from a 2-part, open-label, multicenter phase 1b/2 study (NCT05027139) investigating zanidatamab-hrii (Ziihera), a dual HER2-expressing bispecific antibody, plus the high-affinity CD47 blocker evorpacept in patients with previously treated, unresectable, locally advanced and/or metastatic HER2-expressing breast cancer and other cancers.

Patients eligible for enrollment in this trial needed to have an ECOG performance status of 0 or 1; those with treated, stable brain metastases were permitted to enroll. Cohort 1 (n = 21) included patients with HER2-positive breast cancer who had received at least 3 prior regimens, including trastuzumab (Herceptin), pertuzumab (Perjeta), and 1 of the following: ado-trastuzumab emtansine (Kadcyla), tucatinib (Tukysa), or fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu). Cohort 2 (n = 15) enrolled patients with HER2-low breast cancer that had never been HER2 positive who had received at least 2 prior regimens; prior treatment with T-DXd was allowed. Cohort 3 (n = 8) enrolled patients with HER2-positive gastroesophageal adenocarcinoma or other HER2-overexpressing non-breast cancers. In part b of the trial, patients in the expansion cohorts received the combination at the recommended phase 2 dose of 1200 mg/less than 70 kg or 1600 mg/70 kg or greater of zanidatamab plus 30 mg/kg of evorpacept every 2 weeks of each 28-day cycle.

Alberto Montero, MD, MBA, CPHQ, discusses unmet treatment needs for patients with HER2-positive metastatic breast cancer.

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“The overall response [rate] was around 30%...and progression-free survival [was] around 3 to 4 months, which is still pretty impressive.”

Alberto Montero, MD, MBA, CPHQ, clinical director, Breast Cancer Medical Oncology Program, University Hospitals Seidman Cancer Center; associate professor, medicine, Case Western Reserve University School of Medicine, discusses findings from a phase 1b/2 study (NCT05027139) evaluating zanidatamab-hrii (Ziihera) and evorpacept in HER2-positive and HER2-low metastatic breast cancer (mBC).

In this multicenter study, investigators assessed the safety and efficacy of zanidatamab, a dual HER2-targeted bispecific antibody, in combination with evorpacept, a CD47 blocker, in heavily pretreated patients with HER2-expressing mBC. The median number of prior lines of therapy in the HER2-positive cohort (cohort 1) was 6 (range, 2-10), and all patients with HER2-positive disease had previously received fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu).

2024 San Antonio Breast Cancer Symposium (SABCS)

 highlighted differential outcomes based on HER2 expression levels. Among HER2-positive patients confirmed by central assessment (n = 9), the confirmed overall response rate (cORR) was 55.6% (95% CI, 21.2%-86.3%), and the median progression-free survival (PFS) was 7.4 months (95% CI, 0.6-not evaluable). Across the entirety of cohort 1 (n = 21), which also included patients who were not HER2 positive by central assessment (n = 12), the cORR was 33.3% (95% CI, 14.6%-57.0%), and the median PFS was 3.6 months (95% CI, 1.8-11.0). The cORR and median PFS was 20.0% (95% CI, 4.3%-48.1%) and 1.9 months (95% CI, 1.6-3.9), respectively, in the HER2-low cohort (n = 15).

The combination therapy demonstrated a favorable safety profile, Montero notes. Most adverse effects (AEs) were grade 1 or 2, with diarrhea (61.6%) and infusion-related reactions (23.1%) being the most common. Grade 3 AEs occurred in 13.5% of all patients (n = 52) and included diarrhea (5.8%), fatigue (1.9%), and infusion-related reactions (3.8%). No grade 4 or 5 AEs were reported, and 3.8% of patients discontinued treatment due to AEs. Notably, one patient experienced grade 3 decreased left ventricular ejection fraction, which resolved with intervention.

Mechanistically, the combination leverages zanidatamab’s ability to target HER2-overexpressing tumor cells and evorpacept’s disruption of the CD47 don’t-eat-me signal, enhancing immune-mediated cytotoxicity. These findings underscore the potential of this regimen to address the unmet needs of patients with HER2-expressing mBC who progress on standard therapies, Montero explains.

Although efficacy outcomes were most pronounced in HER2-positive disease, responses were also observed in HER2-low mBC. This suggests the regimen’s broader applicability across varying levels of HER2 expression, Montero concludes. Future studies are warranted to validate these findings and further explore the role of zanidatamab and evorpacept in earlier treatment settings for patients with mBC.

Alberto Montero, MD, MBA, CPHQ, discusses data with the combination of zanidatamab and evorpacept in HER2-positive and HER2-low metastatic breast cancer.

Dr Montero on Zanidatamab and Evorpacept in HER2-Expressing Metastatic Breast Cancer

Alberto Montero, MD, MBA, CPHQ, discusses the mechanism of action and potential advantages of the mutant-selective PI3Kα inhibitor STX-478 in breast cancer.

Dr Montero on Potential Advantages With STX-478 in PI3Kα-Mutant Solid Tumors

Alberto Montero, MD, MBA, CPHQ, clinical director, Breast Cancer Medical Oncology Program, University Hospitals Seidman Cancer Center; associate professor, medicine, Case Western Reserve University School of Medicine, discusses the mechanism of action as well as the potential advantages of treatment with the mutant-selective PI3Kα inhibitor STX-478. He also highlights unmet needs that this agent may address in 

-mutant solid tumors., including breast cancer.

STX-478 is an oral drug that confers several noteworthy advantages across tumor types, Montero begins. Firstly, it has a long half-life, allowing for once-daily dosing and continuous pathway inhibition, as supported by pharmacokinetic data, he states. This extended half-life reduces the need for dose interruptions or reductions due to toxicity, which has been a limitation with other drugs in this class, Montero explains. Additionally, STX-478 is designed to cross the blood-brain barrier, addressing a significant challenge in metastatic breast cancer and other tumors prone to brain metastasis. Montero notes that this enhances its potential as a more effective treatment in these settings.

Another strength of STX-478 is its mutation-specific inhibition of kinase and helical domains, marking a proof of principle for targeted treatment of aberrantly activated pathways in diverse cancers, Montero continues. Although there are other PI3Kα inhibitors approved in breast cancer, the toxicity associated with these agents has limited their use, he says. STX-478’s reduced toxicity profile enables combination with endocrine therapies, presenting a safer and potentially more effective option for patients with 

Beyond breast cancer, STX-478 has also shown single-agent activity in uterine cancer, where 

 mutations are prevalent, Montero reports. Though initial numbers are small, its efficacy is noteworthy, particularly given the limited therapeutic options available for endometrial cancer, he says. As a result, further trials are expected to expand on these early findings, potentially exploring both monotherapy and rational combinations. If the activity holds up, STX-478 may represent a meaningful advance for patients with limited options, particularly in breast and uterine cancers, Montero says. He adds that the agent may also pave the way for improved mutation-specific PI3K inhibition in clinical practice.

Alberto Montero, MD, MBA, CPHQ, discusses the mechanism of action and potential advantages of the mutant-selective PI3Kα inhibitor STX-478 in solid tumors.

Alberto Montero, MD, MBA, CPHQ, clinical director, Breast Cancer Medical Oncology Program, University Hospitals Seidman Cancer Center; associate professor, medicine, Case Western Reserve University School of Medicine, discusses the significance of the FDA approval of elacestrant (Orserdu) in patients with estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer.

On January 27, 2023, the FDA granted approval to elacestrant in adults with ER-positive, HER2-negative, 

-mutated advanced or metastatic breast cancer with disease progression following at least 1 line of endocrine therapy. The approval was supported by findings from the phase 3 EMERALD trial (NCT03778931), in which patients with ER-positive, HER2-negative advanced breast cancer who had received 1 or 2 lines of prior endocrine therapy, including a CDK4/6 inhibitor, were randomized to receive either elacestrant or standard-of-care (SOC) endocrine monotherapy with either aromatase inhibitors or fulvestrant (Faslodex).

Dr. Montero on the Significance of an Oral SERD in Breast Cancer

This approval is significant because elacestrant is the first oral selective estrogen receptor degrader (SERD) to be approved in breast cancer, Montero says. Another SERD, fulvestrant, which is administered through intramuscular injection, is already approved in patients with ER-positive, HER2-negative breast cancer, Montero notes. Additionally, elacestrant is the first agent to be approved for patients in this population with 

 mutations, which are a common mechanism of resistance in ER-positive breast cancer, Montero explains.

Dr. Montero on Key Efficacy Data From EMERALD

In the EMERALD study, treatment with elacestrant prolonged progression-free survival (PFS) in all patients, with a HR of 0.70, Montero says. The respective 6- and 12-month PFS rates were 34.3% and 22.3% in patients who received elacestrant vs 20.4% and 9.4% in patients who received SOC.

 mutations also derived greater benefit from elacestrant, with an HR of 0.55 and 6- and 12-month PFS rates of 40.8% and 26.8% vs 19.1% and 8.2% in patients who received SOC, Montero emphasizes. These positive findings in the population with 

 mutations influenced the indication on the FDA label, Montero says.

When comparing elacestrant to fulvestrant specifically, in the entire study population, the respective 6- and 12-month PFS rates were 34.3% and 22.3% with elacestrant vs 22.9% and 10.2% with fulvestrant. Although elacestrant and fulvestrant are both SERDs, these data show elacestrant to be the more favorable option in patients with ER-positive, HER2-negative breast cancer, regardless of 

Alberto Montero, MD, MBA, CPHQ, discusses the significance of the FDA approval of elacestrant in patients with estrogen receptor–positive, HER2-negative metastatic breast cancer.

Alberto Montero, MD, MBA, CPHQ

Articles

Dr Montero on the Rationale for Evaluating Zanidatamab/Evorpacept in HER2+ Metastatic Breast Cancer

Dr Montero on Unmet Treatment Needs for HER2+ Metastatic Breast Cancer

Dr Montero on Zanidatamab and Evorpacept in HER2-Expressing Metastatic Breast Cancer

Dr Montero on Potential Advantages With STX-478 in PI3Kα-Mutant Solid Tumors

Dr. Montero on the FDA Approval of Elacestrant in ER+/HER2– Breast Cancer