High CD47 Expression Level Predicts Response to Evorpacept/Zanidatamab in HER2+ Breast Cancer

CD47 expression levels were predictive of response to the CD47 inhibitor evorpacept (ALX148) plus zanidatamab-hrii (Ziihera) in heavily pretreated patients with confirmed HER2-positive metastatic breast cancer, according to findings from an exploratory analysis of a phase 1/2 trial (NCT05027139).¹

The full dataset from the phase 1/2 trial have been submitted for presentation at a future scientific meeting.

“These new findings support a CD47-dependent, HER2-driven biology for evorpacept,” Barbara Klencke, MD, chief medical officer at ALX Oncology, stated 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. Additionally, taken together, the data from this trial and the [phase 2/3] ASPEN-06 clinical trial [NCT05002127] reinforce our confidence in the ongoing [phase 2] ASPEN-09-Breast trial [NCT07007559].”

What was the design of the phase 1/2 trial investigating evorpacept plus zanidatamab in HER2-positive metastatic breast cancer?

This trial evaluated the combination in patients with previously treated, unresectable, locally advanced or metastatic HER2-expressing cancers, including breast cancer.^1,2 Patients needed to have an ECOG performance status of 0 or 1.² Those with treated, stable brain metastases were permitted to enroll.

Cohort 1 enrolled patients with HER2-positive breast cancer, defined as immunohistochemistry (IHC) 3+ or IHC 2+ and in situ hybridization positive, who had received at least 3 prior treatment regimens, including trastuzumab (Herceptin); pertuzumab (Perjeta); and ado-trastuzumab emtansine (Kadcyla) or tucatinib (Tukysa) or fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu). Cohort 2 enrolled patients with HER2-low breast cancer, and cohort 3 included those with HER2-positive gastroesophageal adenocarcinoma or other HER2-overexpressing non-breast cancers.

In part 1 safety portion, patients in cohort 1 received zanidatamab at 1200 mg (if weighing < 70 kg) or 1600 mg (if weighing ≥ 70 kg) plus evorpacept at 20 mg/kg (part 1A dose) or 30 mg/kg (part 1B dose) every 2 weeks in 28-day cycles. Patients in cohort 1 in the part 2 expansion portion received the combination at the recommended phase 2 dose, which included the part 1B dose of evorpacept. The primary end point in part 1 was safety. The primary end point in part 2 was confirmed overall response rate (cORR). Key secondary end points in part 2 included progression-free survival (PFS), disease control rate (DCR), duration of response (DOR), and safety.

What data have been previously reported with evorpacept plus zanidatamab in HER2-positive metastatic breast cancer?

Primary findings from the phase 1/2 trial, which were presented at the 2024 San Antonio Breast Cancer Symposium, showed that the combination showed antitumor activity and a safety profile that was deemed manageable among patients with HER2-positive breast cancer who had received a median of 6 prior likes of therapy, including T-DXd. Among the 9 patients in cohort 1 with centrally confirmed HER2-positive breast cancer who received the combination, the cORR was 55.6% (95% CI, 21.2%-86.3%), all of which were PRs. The median PFS was 7.4 months (95% CI, 0.6-not evaluable [NE]), the median DOR was NE (range, 5.6-25.9), and the DCR was 77.8% (95% CI, 40.0%-97.2%).

Data from the exploratory analysis showed that the responses were largely limited to patients with higher levels of CD47 expression.¹

Where else has CD47 expression level shown predictive value in HER2-positive cancers?

The biomarker findings among the patients with breast cancer from the phase 1/2 trial bolster data from the ASPEN-06 trial, which investigated evorpacept plus trastuzumab, ramucirumab (Cyramza), and paclitaxel in patients with advanced, HER2-overexpressing gastric/gastroesophageal junction adenocarcinoma.^1,3 ASPEN-06 also showed that CD47 expression level was predictive of durable response with evorpacept in this patient population.¹

What’s next for evaluating evorpacept in HER2-positive breast cancer?

The ongoing ASPEN-09 trial is investigating evorpacept in combination with other anticancer therapies in patients with advanced or metastatic cancers.⁴ The single-arm ASPEN-09-Breast substudy is evaluating the efficacy, safety, and tolerability of evorpacept plus trastuzumab and chemotherapy in patients with HER2-positive metastatic breast cancer who have been previously treated with T-DXd.

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 Holdings Inc. January 30, 2026. Accessed March 11, 2026. https://ir.alxoncology.com/news-releases/news-release-details/new-data-demonstrate-cd47-expression-level-helps-predict/
2. Montero AJ, Wisinski KB, Fang B, et al. Zanidatamab in combination with evorpacept in HER2-positive and HER2-low metastatic breast cancer: results from a phase 1b/2 study. Presented at: 2024 San Antonio Breast Cancer Symposium. December 10-13, 2024. San Antonio, Texas. PS8-09
3. A study of evorpacept (ALX148) in patients with advanced HER2+ gastric cancer (ASPEN-06). ClinicalTrials.gov. Updated August 7, 2025. Accessed March 11, 2026. https://clinicaltrials.gov/study/NCT05002127
4. 4.ASPEN-09: a study of evorpacept in combination with anti-cancer therapies in advanced /​ metastatic malignancies (ASPEN-09). ClinicalTrials.gov. Updated February 3, 2026. Accessed March 11, 2026. https://clinicaltrials.gov/study/NCT07007559