Dr Krop on Zanidatamab Plus Evorpacept in HER2+ Metastatic Breast Cancer

"A molecule that I wanted to highlight is [a bispecific] antibody that binds to two different molecules on two different epitopes on [HER2]. So [technically], it's a [biparatopic] antibody, but by binding to two separate epitopes on [HER2], it's able to cause differences in internalization and [potentially enhance the] immune response. [Early data on] this drug, [zanidatamab], [suggests] activity in [pretreated] HER2-positive disease."

Ian Krop, MD, PhD, director, Clinical Trials Office, chief clinical research officer, associate director, Clinical Sciences, Yale Cancer Center, discusses findings from a phase 1b/2 study (NCT05027139) evaluating zanidatamab-hrii (Ziihera) in combination with evorpacept (ALX148) in HER2-positive and HER2-low metastatic breast cancer (mBC), presented at the 2024 San Antonio Breast Cancer Symposium (SABCS).

In this open-label, multicenter study, investigators assessed the safety and efficacy of zanidatamab, a biparatopic HER2-targeted bispecific antibody, in combination with evorpacept, a CD47-blocking agent designed to enhance antibody-mediated cellular phagocytosis. The study enrolled heavily pretreated patients. Notably, all patients in the HER2-positive mBC cohort (cohort 1) had progressed on prior fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) vs 33.3% of those in the HER2-low mBC cohort (cohort 2). In cohort 1 (n = 21), among patients with HER2 positivity 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).

Mechanistically, Krop explains that zanidatamab exerts antitumor activity through dual epitope binding on HER2, promoting enhanced receptor internalization and immune activation. By blocking CD47, evorpacept is hypothesized to further augment antitumor activity via increased macrophage-mediated phagocytosis of HER2-overexpressing tumor cells. The study aimed to determine whether this combination could yield synergistic therapeutic effects in a refractory setting.

Krop notes that the contribution of each agent remains unclear. However, the observed response rate suggests potential efficacy in a population with limited treatment options, reinforcing the rationale for further investigation, particularly in the post-T-DXd setting, where there remains a need for effective therapeutic alternatives.

Krop concludes that although preliminary, these findings suggest that dual HER2 targeting combined with immune modulation may represent a promising therapeutic strategy for heavily pretreated patients with HER2-positive breast cancer. Continued research will be essential to refine patient selection criteria and establish the regimen’s role in clinical practice.