CD47-Targeted Evorpacept Shows Durable Responses in HER2+ Gastric Cancer

Adding the CD47-blocking agent evorpacept to trastuzumab (Herceptin), ramucirumab (Cyramza), and paclitaxel (TRP) resulted in higher response rates and more durable benefit than chemotherapy plus targeted therapy alone in patients with previously treated HER2-positive advanced gastric or gastroesophageal junction (GEJ) cancer, according to findings from the randomized phase 2/3 ASPEN-06 trial (NCT05002127) published in Nature Medicine.¹

Among the 127 adult patients enrolled in the phase 2 portion of the trial, the evorpacept combination yielded an objective response rate (ORR) of 40.3%, compared with 26.6% among patients who received the control regimen of TRP alone, in the intent-to-treat (ITT) population.

The benefit was more pronounced among patients confirmed to have retained HER2-positive disease verified through a tumor biopsy or detection of ERBB2 gene amplification in circulating tumor DNA (ctDNA). In this subgroup, ORR rose to 48.9% with the evorpacept combination vs 25.0% with TRP alone.

ASPEN-06 Trial Design

ASPEN-06 is an international, multicenter, randomized phase 2/3 study evaluating evorpacept plus TRP against TRP alone in patients with metastatic second- or third-line HER2-overexpressing gastric or GEJ adenocarcinoma who had disease progression on prior HER2-directed therapy and fluoropyrimidine- or platinum-containing chemotherapy. Patients were randomly assigned on a 1:1 basis and baseline patient characteristics were described as balanced across the treatment arms. All patients had received a HER2-directed therapy as first- or second-line treatment; 73.2% had received only 1 prior line of therapy and 14.2% had received prior trastuzumab deruxtecan (Enhertu).

Patients received an all-intravenous regimen of 30 mg/kg evorpacept every 2 weeks with trastuzumab and ramucirumab, with paclitaxel once weekly for the first 3 weeks of every 28-day cycle.

The primary efficacy end point was investigator-assessed ORR per RECIST v1.1, with secondary end points including ORR by blinded independent central review, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Exploratory end points included an analysis of CD47 as a predictive or prognostic biomarker.

Key Findings From ASPEN-06

At the data cutoff of May 24, 2024, the median follow-up was 7.8 months. Ninety-five patients (74.8%) were identified as having HER2-positive status, 47 (37.0%) by fresh biopsy and 86 (67.7%) by ctDNA. The differences in ORR between treatment arms met the prespecified difference to establish clinically meaningful efficacy of evorpacept. The 40.3% ORR in the ITT population and 54.8% ORR in those who had HER2-positive status confirmed by fresh biopsy exceeded the historical benchmark of 30% but did not meet the prespecified statistical success criterion of 1-sided α of 0.025 (P = .0949 and P = .030, respectively) and failed to reach this second primary end point.

At the primary analysis, the median DOR was 15.7 months for evorpacept plus TRP vs 7.6 months for TRP alone by investigator assessment in both the ITT population and the HER2-positive fresh biopsy population. Median PFS was 7.5 months vs 7.5 months in the ITT population and 9.0 months vs 7.4 months in the fresh biopsy subgroup, respectively. OS data were not mature at this time point.

At a longer follow-up as of May 15, 2025, efficacy outcomes were consistent with the primary analysis with a PFS HR of 0.87 in the ITT population and 0.70 in the fresh biopsy HER2-positive subgroup both favoring the evorpacept arm; OS was similar in both arms (HR, 1.07; 95% CI, 0.69-1.66) in the ITT population and in the fresh biopsy HER2-positive group (HR, 1.05; 95% CI, 0.46-0.238).

In terms of safety, the most common treatment-emergent adverse events (TEAEs) were neutropenia, anemia, and diarrhea, each of which were more common in the evorpacept arm. Grade 3 or higher TEAEs occurred in 90.5% of those receiving evorpacept and 79.4% of those receiving TRP alone; these were most commonly neutropenia, anemia, or leukopenia. There were 5 fatal TEAEs in the evorpacept arm and 7 in the TRP alone arm; 2 in the evorpacept arm and 1 in the TRP alone arm were considered potentially treatment related, though none associated with evorpacept treatment.

CD47 Expression as a Predictive Biomarker

Post hoc biomarker analyses identified CD47 expression as a potential predictive marker of response to evorpacept; similar findings were reported in a study of HER2-positive breast cancer.² Among patients with both retained HER2 positivity and high CD47 expression (defined as ≥5% CD47 IHC 3+ staining), the evorpacept combination produced an ORR of 63.6%, compared with 23.1% for TRP alone. This subgroup also showed improved median progression-free survival (19.5 months vs 7.0 months) and median duration of response (25.5 months vs 8.4 months) favoring the evorpacept arm. No benefit was seen with evorpacept in patients who did not have confirmed HER2 positivity after prior HER2-directed treatment, regardless of CD47 status, although some of these patients had no fresh biopsy to confirm HER2 expression loss.

High CD47 expression was also associated with a trend toward shorter PFS (HR, 1.42; 95% CI, 0.70-2.85) and OS (HR, 1.54; 95% CI, 0.73-3.22) in the TRP arm compared with low CD47 expression.

Investigators stated that the results support the proposed mechanism that both retained HER2 expression and elevated CD47 levels may drive efficacy through enhanced antibody-dependent cellular phagocytosis, and that CD47-guided patient selection warrants further evaluation in future studies.

“Data from ASPEN-06 demonstrated that patients whose tumors retained HER2 expression and had high CD47 expression experienced the greatest benefit from evorpacept-based therapy, supporting our hypothesis that evorpacept can enhance the activity of HER2-directed treatment regimens and highlights CD47 expression as a potential predictive biomarker,” Barbara Klencke, MD, chief medical officer of ALX Oncology, stated in a news release.³

No Plans for Registrational Path in Gastric Cancer

Although Klencke said that the publication reinforces the strategy of targeting CD47 and the potential of evorpacept, ALX Oncology stated that it will not pursue a US registrational path with a phase 3 trial in gastric cancer, citing resource allocation priorities, and will instead consider development partnerships to advance the program in that indication.

The company said the ASPEN-06 findings reinforce its ongoing phase 2 ASPEN-09-Breast trial (NCT07007559), which is evaluating evorpacept in combination with trastuzumab and chemotherapy in patients with HER2-positive metastatic breast cancer. Topline data from 80 patients in that trial remain on track for a readout in mid-2027.

REFERENCES

1. ALX Oncology Announces Nature Medicine Publication of ASPEN-06 Phase 2 Clinical Data Demonstrating Strong Responses and Durable Clinical Benefit with Evorpacept in HER2-Positive Gastric Cancer. News release. ALX Oncology. September 28, 2026. Accessed September 29, 2026. https://tinyurl.com/yc69t7br

2. 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 September 29, 2026. https://tinyurl.com/mpn2b36f

3. Shitara K, Wainberg Z, Tabernero J, et al. Evorpacept plus trastuzumab, ramucirumab and paclitaxel in HER2-positive gastric cancer: a randomized phase 2 trial. Nat Med. Published September 24, 2026. doi:10.1038/s41591-026-04700-3