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

“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).

Results presented at the 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.