ASPEN-09-03 Trial Aims to Build the Case for Evorpacept in Post–T-DXd HER2+ Breast Cancer

Evorpacept (ALX148), an investigational CD47-directed myeloid checkpoint inhibitor engineered with an inactive Fc domain, may expand the efficacy of HER2-directed therapy in patients with metastatic breast cancer who have progressed on fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), particularly when circulating tumor DNA (ctDNA) assays and CD47 expression are used to select patients most likely to respond, according to Sara A. Hurvitz, MD, FACP, and Javier Cortés, MD, PhD.

The phase 2 ASPEN-09-03 trial (NCT07007559) is evaluating evorpacept in combination with trastuzumab (Herceptin) and physician’s choice of chemotherapy in patients with HER2-positive metastatic breast cancer whose disease has progressed after T-DXd.¹ This research builds on findings from an exploratory biomarker analysis of the phase 1b/2 trial (NCT05027139) of the HER2-targeted bispecific antibody zanidatamab-hrii (Ziihera) plus evorpacept in patients with HER2-positive metastatic breast cancer.²

“To understand evorpacept, we first have to understand the target,” Hurvitz said in an exclusive interview with OncLive®. “CD47 is a checkpoint on myeloid cells, sending a signal to macrophages not to eat the cancer cell. If you block that signal…you can improve the immune responsiveness to therapies that are targeting cancer.”

Hurvitz is 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 in Seattle.

Cortés is head of the International Breast Cancer Center in Barcelona, Spain.

What is the rationale for targeting CD47 in HER2-positive breast cancer?

HER2-directed antibody-drug conjugates, such as T-DXd, have reshaped the management of HER2-positive metastatic breast cancer, but most patients with metastatic disease eventually progress, and options after T-DXd remain limited, Cortés emphasized in another interview with OncLive.

CD47 is a cell surface protein upregulated on tumor cells that engages signal regulatory protein alpha on macrophages to transmit a “don’t-eat-me” signal and suppress phagocytosis.² Evorpacept is a high-affinity CD47 blocker with an inactive Fc domain designed to disrupt the CD47–SIRPα interaction and enhance antibody-dependent cellular phagocytosis in combination with other antibodies, simultaneously avoiding the toxicities associated with conventional CD47-targeted agents.

“CD47 is a tumor marker, detected by immunohistochemistry, that is [thought to be] a mechanism of resistance to T-DXd [and other] anti-HER2 therapies,” Cortés said. “When you give trastuzumab or anti-HER2 therapies, you might increase the tumor cells’ expression of CD47.”

What data have been seen with zanidatamab plus evorpacept in HER2-expressing metastatic breast cancer?

The exploratory biomarker analysis of the phase 1b/2 trial evaluated zanidatamab plus evorpacept in 24 patients with HER2-expressing metastatic breast cancer, 10 of whom had centrally confirmed HER2-positive disease per central immunohistochemistry and fluorescence in situ hybridization. Patients had received a median of 5 prior HER2-targeted therapies (range, 3-7), and all had received prior T-DXd. Three patients received evorpacept at 20 mg/kg, and 21 patients received the agent at 30 mg/kg, both in combination with zanidatamab.

Across all patients, the confirmed overall response rate (ORR) was 33.3%, and the median progression-free survival (PFS) was 3.6 months (95% CI, 1.7-11.0). In patients with centrally confirmed HER2-positive disease (n = 10), the confirmed ORR was 60.0%, and the median PFS was 8.3 months (95% CI, 0.6-not estimable [NE]). The activity of the combination was further concentrated with higher CD47 expression: all 5 patients with centrally confirmed HER2-positive disease and CD47 expression of at least 20% achieved a complete or partial response, with a median duration of response of 20.2 months (95% CI, 5.6-NE). In that centrally confirmed subgroup, the median PFS was 22.1 months (95% CI, 7.4-NE) among patients with CD47 expression of at least 20% vs 3.4 months (95% CI, 1.5-NE) in those with CD47 expression below 20%.

“When we look at CD47 and combine both centrally confirmed HER2- and CD47[-positive disease], all but 1 patient had a great response,” Cortés said. “It was a small number of patients, but the activity seems to be amazing.”

Hurvitz further characterized the HER2-positive/CD47-positive subgroup as the population with the central signal, saying, “Although it was only [in] 5 patients, those results are encouraging and provide the rationale for the ongoing ASPEN-09-03 study.”

Additionally, analyses of plasma ctDNA supported HER2-driven disease biology in responders. Central tissue HER2 positivity and ERBB2 amplification on ctDNA next-generation sequencing showed 86% concordance, and patients with a complete or partial response to the combination had greater than 90% on-treatment reductions in ERBB2 copy number.

How is the ASPEN-09-03 trial designed?

ASPEN-09-03 is a single-arm, open-label, multicenter substudy of the ASPEN-09 master protocol evaluating evorpacept plus trastuzumab and physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or vinorelbine) in patients with HER2-positive metastatic breast cancer.¹

The trial plans to enroll 120 patients with histologically confirmed invasive HER2-positive breast cancer who have received at least 1 prior line of therapy, including T-DXd for locally advanced or metastatic disease; have progressed on or after their most recent line of therapy; have measurable disease per RECIST 1.1 criteria; have a left ventricular ejection fraction of at least 50%; and have an ECOG performance status of 0 or 1.

The primary end point of the trial is ORR in the subpopulation of patients confirmed to have HER2-positive and CR47-expressing disease, with key secondary end points of ORR, clinical benefit rate, duration of response, PFS, and overall survival in the subpopulation of patients with HER2-positive and CD47-expressing disease; as well as safety.

“All patients receive the 3 drugs, so there is no randomization,” Cortés explained. “We are requiring, for the majority of patients, a baseline biopsy, because we want to look at CD47 [expression],” he said. “The main objective of this study is to [provide] the basis for [a] pivotal trial afterwards.”

The first patient was dosed in January 2026, and interim data are expected to be released in the third quarter of 2026.³

What could continued positive data with evorpacept mean for the HER2-positive cancer treatment paradigm?

If the ASPEN-09-03 findings are positive, Hurvitz and Cortés emphasized that this readout may support the introduction of CD47 as an additional biomarker to layer onto HER2 status when selecting therapy for pretreated breast cancer. The two also predicted that this agent may be a treatment option for patients who have exhausted T-DXd. Cortés noted that patients in the second-line setting and beyond are currently treated on the basis of HER2 status alone, and that a validated CD47 readout could allow treatment to be tailored more precisely and expand the number of available treatment options.

“We have little in the way of evidence about what works after T-DXd,” according to Hurvitz. “Seeing a therapy emerge that may have benefit after a patient’s disease has progressed on T-DXd is going to be valuable, since we’re using [T-DXd] now in the frontline setting for metastatic disease, and [it] got an approval [in May 2026] for early-stage disease.”

Support for the use of evorpacept extends beyond breast cancer. In the randomized phase 2 portion of the ASPEN-06 trial (NCT05002127) in patients with HER2-positive gastric or gastroesophageal junction cancer, adding evorpacept to trastuzumab, ramucirumab (Cyramza), and paclitaxel (TRP) increased the confirmed ORR to 41.3% (n = 63; 95% CI, 29.0%-54.4%) vs 26.6% (95% CI, 16.3%-39.1%) with TRP alone (n = 64) in the intention-to-treat population.⁴ Among patients with HER2-positive disease confirmed by fresh biopsy or ctDNA (n = 96), the confirmed ORRs were 48.9% (n = 47; 95% CI, 34.1%-63.9%) vs 24.5% (n = 49; 95% CI, 13.3%-38.9%), respectively, and a PFS benefit was seen with the evorpacept-based combination in this population (HR, 0.64; 95% CI, 0.39-1.07).

Notably, ASCO’s first guideline on ctDNA testing in solid tumors, issued in August 2026, reflects the broader movement of the cancer field toward the plasma-based HER2 confirmation that anchors the ASPEN-09-03 primary end point.⁵

References

1. ASPEN-09-03: a study of evorpacept in combination with trastuzumab and chemotherapy in metastatic HER2-positive breast cancer. ClinicalTrials.gov. Updated August 14, 2026. Accessed August 26, 2026. https://clinicaltrials.gov/study/NCT07007559
2. Meric-Bernstam F, Wisinski KB, Fang B, et al. Exploratory biomarker analysis from a phase 1b/2 trial of zanidatamab + evorpacept in patients with HER2-positive metastatic breast cancer. Ann Oncol. 2026;11(suppl 4):1-61. doi:10.1016/esmoop/esmoop106965
3. ALX Oncology advances separate clinical trials evaluating investigational CD47-inhibitor evorpacept and novel EGFR-targeted antibody-drug conjugate ALX2004. News release. ALX Oncology Holdings Inc. January 8, 2026. Accessed August 26, 2026. https://ir.alxoncology.com/node/10701/pdf
4. Shitara K, Wainberg Z, 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. 2025;43(suppl 4):332. doi:10.1200/JCO.2025.43.4_suppl.332
5. Lockwood CM, Messersmith HJ, Kim AS, et al. Circulating tumor DNA testing in solid tumors and lymphoma: ASCO guideline. JCO Oncol Pract. Published online June 18, 2026. doi:10.1200/OP-26-00311