CD47 Expression Serves as Predictive Biomarker for HER2+ Breast Cancer

New exploratory data from a phase 1b/2 clinical trial (NCT05027139) suggest that CD47 expression levels may serve as a critical predictive biomarker for the efficacy of evorpacept (ALX148) in patients with heavily pretreated HER2-positive metastatic breast cancer. The findings indicate that clinical activity of the investigational CD47 blocker in combination with zanidatamab-hrii (Ziihera) is largely restricted to patients with elevated CD47 expression.¹

Exploratory Analysis and Biomarker Correlation

The exploratory analysis followed primary results previously reported at the 2024 San Antonio Breast Cancer Symposium. While the initial data demonstrated promising antitumor activity in a difficult-to-treat population, this new subset analysis clarifies the role of tumor biology in mediating response.

"These new findings support a CD47-dependent, HER2-driven biology for evorpacept," said Barbara Klencke, MD, chief medical officer at ALX Oncology, in a news release. "Going forward, we believe that a biomarker-driven approach incorporating CD47 expression may optimize patient selection for evorpacept combinations with HER2-targeted agents.”

These findings mirror results observed in the ASPEN-06 trial (NCT04771247), which evaluated evorpacept in advanced HER2-positive gastric and gastroesophageal junction cancers.² In that study, a higher tumor proportion score for CD47 was similarly associated with improved clinical outcomes, suggesting a consistent biomarker signal across different HER2-expressing solid tumors.

Efficacy in Heavily Pretreated Populations

The phase 1b/2 multi-center, open-label trial evaluated evorpacept in combination with zanidatamab, a HER2-targeted bispecific antibody.¹ The study population was notably late line, with patients having received a median of 6 prior systemic therapies. This included progression on standard-of-care agents such as trastuzumab deruxtecan (T-DXd; Enhertu).

In the 9 patients with centrally confirmed HER2-positive metastatic breast cancer who received the combination, the confirmed objective response rate was 56% (n = 5/9). The median progression-free survival (mPFS) reached 7.4 months.

Given the exhaustion of standard therapeutic options in this cohort, the observed mPFS and response rate represent a significant signal of activity for an immunotherapy-based combination in a cold tumor environment.

Mechanism of Action: Overcoming "Don't Eat Me" Signals

Evorpacept is an engineered high-affinity SIRPα fusion protein designed to block the CD47-SIRPα "don't eat me" signaling pathway.³ Unlike earlier-generation CD47 inhibitors, evorpacept features an inactive Fc domain. This design aims to minimize off-target binding to healthy cells, such as red blood cells and platelets, thereby reducing the incidence of treatment-induced anemia and thrombocytopenia.

In HER2-positive disease, the combination of evorpacept and zanidatamab is hypothesized to create a synergistic effect.¹ Zanidatamab facilitates tumor cell opsonization and induces antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. By concurrently blocking the CD47 signal, evorpacept removes the inhibitory signal on macrophages, potentially amplifying the phagocytic clearance of tumor cells initiated by the HER2-targeted agent.

Clinical Implications and Future Directions

The shift toward a biomarker-driven approach reflects a broader trend in oncology to optimize patient selection for innate immune checkpoints. The full biomarker analysis from the phase 1b/2 trial is expected to be presented at an upcoming scientific congress. As the clinical development of evorpacept progresses, the focus will likely remain on validating the CD47 expression threshold required to maximize the therapeutic index in combination with other targeted therapies.

REFERENCES

1. New data demonstrate CD47 expression level helps predict response to ALX oncology’s evorpacept in combination with Ziihera (zanidatamab-hrii) in advanced HER2-positive breast cancer. News release. ALX Oncology. January 30, 2026. Accessed February 2, 2026. https://tinyurl.com/mpn2b36f

2. Shitara K, Wainberg ZA, Tabernero J, et al. Final analysis of the randomized phase 2 part of the ASPEN-06 study: A phase 2/3 study of evorpacept (ALX148), a CD47 myeloid checkpoint inhibitor, in patients with HER2-overexpressing gastric/gastroesophageal cancer (GC). J Clin Oncol 43, 332-332(2025). doi:10.1200/JCO.2025.43.4_suppl.332

3. Evorpacept: a cornerstone of future oncology therapy. ALX Oncology. Accessed February 2, 2026. https://tinyurl.com/3ktz24vn