Evorpacept Plus TRP Improves ORR in Pretreated HER2+ Gastric Cancer

Adding evorpacept, an investigational CD47-blocking fusion protein, to trastuzumab (Herceptin), ramucirumab (Cyramza), and paclitaxel (TRP) improved the objective response rate (ORR) vs TRP alone in patients with pretreated HER2-positive advanced gastric or gastroesophageal junction (GEJ) cancer, according to the phase 2 portion of the randomized phase 2/3 ASPEN-06 trial (NCT05002127) published in Nature Medicine.¹

What were the efficacy results in the ASPEN-06 phase 2 portion?

In the protocol-defined primary analysis with a data cutoff of May 24, 2024, and a median follow-up of 7.8 months, the investigator-assessed ORR was 40.3% (95% CI, 28.1%-49.3%; n = 24/63) with evorpacept plus TRP vs 26.6% (95% CI, 16.3%-39.1%; n = 17/64) with TRP alone in the ITT population. In the prespecified subgroup with a fresh HER2-positive biopsy, the ORRs were 54.8% (95% CI, 32.3%-66.3%; n = 12/22) vs 23.1% (95% CI, 9.0%-43.6%; n = 6/26), respectively. The regimen did not meet the prespecified statistical criterion for the trial's primary comparison against a historical benchmark.

The between-arm ORR differences (13.7% in the ITT population and 31.7% in the fresh biopsy subgroup) exceeded the prespecified thresholds of 8% and 9.7%, meeting 1 of the trial's 2 primary objectives. However, the ORRs compared with the historical 30% benchmark for ramucirumab plus paclitaxel (ITT, P = .0949; fresh biopsy subgroup, P = .030; both 1-sided) did not meet the prespecified 1-sided α of .025, so that primary end point was not met.

The median duration of response (DOR) was 15.7 months with evorpacept plus TRP vs 7.6 months with TRP alone in both populations. The median progression-free survival (PFS) was 7.5 (95% CI, 5.4-12.9) vs 7.4 months (95% CI, 4.6-9.0) in the ITT population and 9.0 (95% CI, 5.4-not reached [NR]) vs 7.4 months (95% CI, 2.9-9.1) in the fresh biopsy subgroup. Overall survival (OS) data were not mature at the primary analysis; in the updated analysis (data cutoff, May 15, 2025), and the OS was similar between arms (ITT HR, 1.07; 95% CI, 0.69-1.66).

What did the post hoc biomarker analyses show for HER2 and CD47?

In post hoc analyses of the updated data, 95 patients (74.8%) had retained HER2-positive disease, defined by HER2 positivity on a fresh biopsy or ERBB2 amplification in baseline circulating tumor DNA (ctDNA). In this subgroup, the ORR was 48.9% with evorpacept plus TRP vs 25.0% with TRP alone; the HRs were 0.72 (95% CI, 0.44-1.18) for PFS and 0.95 (95% CI, 0.58-1.56) for OS.¹

Among 90 patients with retained HER2-positive disease who were evaluable for CD47, those with CD47-high tumors (at least 5% of tumor cells with membrane immunohistochemistry 3+ staining; n = 48) had an ORR of 63.6% (n = 14/22) with evorpacept plus TRP vs 23.1% (n = 6/26) with TRP alone. The median DOR was 25.5 (95% CI, 7.4-NR) vs 8.4 months (95% CI, 6.3-NR; HR, 0.27; 95% CI, 0.07-1.06); the median PFS was 19.5 (95% CI, 5.6-31.0) vs 7.0 months (95% CI, 3.7-9.0; HR, 0.38; 95% CI, 0.17-0.84), and the OS HR was 0.66 (95% CI, 0.32-1.37).¹ In patients with CD47-low tumors (n = 42), the ORRs were similar between arms (36.4% vs 30.0%), and HRs favored TRP alone for PFS (1.48; 95% CI, 0.73-3.01) and OS (1.74; 95% CI, 0.81-3.72). No benefit was observed among the 32 patients who did not meet the definition of retained HER2-positive disease (ORR, 18.8% vs 31.3%).

The 5% CD47 cutoff was derived and evaluated in the same dataset, and the study was not powered to detect treatment-by-CD47 interactions; unadjusted interaction P values were 0.161 for ORR, 0.006 for PFS, and 0.039 for OS.

“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,” stated Barbara Klencke, MD, chief medical officer of ALX Oncology, in a press release.²

What safety findings were reported with evorpacept plus TRP?

Any-grade treatment-emergent adverse events (TEAEs) occurred in 100% of patients in both arms (n = 63 each). The most common TEAEs with evorpacept plus TRP vs TRP alone were neutropenia (69.8% vs 55.6%), anemia (58.7% vs 38.1%), and diarrhea (41.3% vs 36.5%). Grade 3 or higher TEAEs occurred in 90.5% vs 79.4% of patients, most commonly neutropenia (55.6% vs 39.7%), anemia (23.8% vs 17.5%), and leukopenia (17.5% vs 9.5%); febrile neutropenia occurred in 2 patients (3.2%) vs 5 patients (7.9%).

Grade 5 TEAEs occurred in 5 patients in the evorpacept arm and 7 in the TRP arm. Three grade 5 treatment-related events were reported: 2 in the evorpacept arm, neither considered related to evorpacept, and 1 in the TRP arm. TEAEs led to evorpacept discontinuation in 5 patients (7.9%). The investigators described hematologic toxicities as more common with evorpacept plus TRP but overall safety as similar between arms.

How was the ASPEN-06 phase 2 portion designed?

ASPEN-06 is an international, multicenter, randomized phase 2/3 study; the phase 2 portion was open label. Between February 2022 and January 2024, 127 patients across 49 institutions in 10 countries were randomized 1:1 to evorpacept (30 mg/kg), trastuzumab (6 mg/kg initially, then 4 mg/kg), and ramucirumab (8 mg/kg) every 2 weeks plus weekly paclitaxel (80 mg/m²) for the first 3 weeks of each 28-day cycle (n = 63), or to TRP alone (n = 64).¹

Eligible patients had HER2-positive advanced or metastatic gastric/GEJ adenocarcinoma that had progressed on or after HER2-directed therapy and/or fluoropyrimidine- or platinum-containing chemotherapy; prior ramucirumab and prior anti-CD47 or anti-SIRPα agents were exclusion criteria. The median age was 64 years, 82.7% of patients had HER2 immunohistochemistry 3+ disease, 73.2% were receiving second-line therapy, 14.2% had received prior trastuzumab deruxtecan (Enhertu), and 21.3% had received prior anti–PD-1 therapy. The primary end point was investigator-assessed ORR.

References

1. 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 online September 24, 2026. doi:10.1038/s41591-026-04700-3
2. 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 Holdings Inc. September 28, 2026. Accessed September 28, 2026. https://tinyurl.com/347up67c