Dr Hurvitz on Evorpacept Plus Zanidatamab in Pretreated HER2+ Metastatic Breast Cancer

“Cancer cells can express CD47 on [their] surface, and it sends a signal to macrophages not to eat the cancer cell. The thought is, if you block that CD47 signal with a drug [like evorpacept], then you can improve the immune responsiveness to therapies that are targeting cancer.”

Sara A. Hurvitz, MD, FACP, senior vice president and director of the Clinical Research Division, the Smith Family Endowed Chair in Women’s Health, and an affiliate investigator in the Translational Science and Therapeutics Division at the Fred Hutchinson Cancer Center; as well as head of the Division of Hematology and Oncology at the University of Washington School of Medicine, discussed the rationale for and findings from a phase 1b/2 trial (NCT05027139) evaluating the CD47 inhibitor evorpacept (ALX148) in combination with the bispecific HER2-directed antibody zanidatamab-hrii (Ziihera) in patients with heavily pretreated HER2-positive metastatic breast cancer.

Hurvitz began by explaining that evorpacept is a fusion protein directed against the CD47:SIRPα myeloid checkpoint. Cancer cells can display CD47 on their surface, signaling to macrophages not to engulf them; blocking that signal is thought to enhance immune responsiveness to cancer-directed therapies, she noted. Hurvitz emphasized that prior CD47 blockade attempts have been complicated by cytopenias, as an active Fc domain can engage macrophages and trigger consumption of normal cells. Evorpacept was consequently engineered with an inactive Fc portion to avoid this toxicity, she explained.

Notably, evorpacept has also been evaluated in patients with HER2-overexpressing gastric/gastroesophageal cancer in the phase 2/3 ASPEN-06 trial (NCT05002127), in which the addition of evorpacept to trastuzumab (Herceptin) plus ramucirumab (Cyramza) and paclitaxel generated a higher overall response rate (ORR) and median duration of response (DOR) compared with trastuzumab plus ramucirumab and paclitaxel alone. The evorpacept-based combination performed best in tumors that were deemed HER2 positive based on fresh biopsies or amplification in ctDNA and had high CD47 expression.

Turning to the phase 1b/2 breast cancer study design, Hurvitz stated that patients with HER2-positive breast cancer who had received at least 3 prior regimens, including trastuzumab, pertuzumab (Perjeta), and other agents, were eligible to enroll and received zanidatamab plus evorpacept, with evorpacept administered at 2 dose levels every 2 weeks in 28-day cycles. These heavily pretreated patients had received a median of approximately 5 (range, 3-7) prior HER2-targeted therapies and had prior trastuzumab deruxtecan (Enhertu) exposure, she noted.

The ORR was 33.3% across all patients (n = 24), Hurvitz reported. However, among the 10 patients with centrally confirmed HER2-positive disease, the ORR rose to 60.0%, with a median DOR of 20.2 months (95% CI, 5.6-not evaluable [NE]) and a median progression-free survival of 8.3 months (95% CI, 0.6-NE).

Hurvitz further highlighted a biomarker analysis showing that patients with CD47 expression on at least 20% of tumor cells derived the greatest benefit, including a 100% ORR among the 5 patients with both centrally confirmed HER2-positive and CD47-positive disease. Although these biomarker findings were limited to 5 patients, they provide the rationale for the ongoing ASPEN-09-03 study (NCT07007559), which is investigating evorpacept plus trastuzumab and chemotherapy in patients with metastatic HER2-positive breast cancer, Hurvitz concluded.