Evorpacept: A New Treatment for HER2-Positive Gastric and Gastroesophageal Junction Cancer

Approximately 15-20% of gastric and gastroesophageal junction cancers are known to be HER2-positive. This means that HER2-positive tumors produce more HER2 protein than normal on the cell surface or have mutations in the HER2 gene. This is associated with faster tumor growth and a tendency to metastasize. HER2 positivity allows these patients to benefit from HER2-targeted treatments specifically designed for them. By inhibiting tumor growth, these treatments can prolong survival and improve disease control. Identifying HER2 positivity is crucial to treatment planning.

A New Treatment Option

For HER2-positive gastric and gastroesophageal junction (GEJ) cancers, evorpacept is an immunotherapy with an innovative design. A new regimen incorporating this agent offers substantially better results than the existing treatment.

The median duration of response was 15.7 months in the evorpacept arm and 9.1 months in the control arm.

The 2025 ASCO Gastrointestinal Cancers Symposiumfeatured the findings under #ASCOGI25. Adding evorpacept, a CD47-targeted treatment, to the combination of trastuzumab, ramucirumab and paclitaxel (TRP) improved response rates and progression-free survival (PFS) .

How Does Evorpacept Work?

Evorpacept targets a protein called CD47 on the surface of cancer cells and is an immunotherapy agent. CD47 is recognized by the immune system’s phagocytic cells as a “don’t eat me” signal, helping cancer cells evade immune defenses. By blocking CD47, evorpacept inhibits this signal and allows the immune system to recognize and destroy cancer cells.

Is It an Approved Drug?

Evorpacept is an immuno-oncology drug developed by the US biotechnology company ALX Oncology. It is being evaluated in clinical trials for several cancers. According to the information currently available, however, it has not yet received official approval in any country. It may be approved in the future, depending on the results of clinical trials.

The ASPEN-06 Trial: New Horizons in Treatment

The phase 2/3 ASPEN-06 trial included patients with HER2-positive gastric/GEJ cancer who had previously received first- or second-line treatment and whose disease had progressed after anti-HER2 therapy.

A total of 127 patients were randomly assigned to two groups:

• Evorpacept + TRP (63 patients)

• TRP alone (64 patients).

Patient Profile

• Median age: 64 in the evorpacept group (range, 34-81) and 63 in the control group (range, 31-86).

• Approximately half of the patients were Asian (49.2% and 48.4%).

• Most patients had gastric cancer (76.2% and 68.8%).

• Most had previously received only one line of treatment (77.8% and 68.8%).

Treatment Efficacy: Longer Responses

Response rates and response durations with evorpacept + TRP were better than in the control group:

• Objective response rate: Evorpacept group 41.3%, TRP group 26.6%.

  • 1 complete response was observed in each group.

  • There were 25 partial responses in the evorpacept group and 16 in the control group.

• Median duration of response: 15.7 months in the evorpacept group and 9.1 months in the TRP group.

Progression-Free Survival (PFS): A Small Advantage

• Median PFS: 7.5 months in the evorpacept group and 7.4 months in the TRP group (HR, 0.77; 95% CI, 0.49-1.20).

Stronger Results With Confirmed HER2 Positivity

Treatment efficacy was more pronounced in subgroups with HER2 positivity confirmed by a fresh biopsy or circulating tumor DNA (ctDNA):

• Fresh-biopsy HER2-positive subgroup:

  • Objective response rate: 59.1% in the evorpacept group and 23.1% in the TRP group.

  • Median duration of response: 15.7 months and 14.5 months.

  • Median PFS: 9.5 months and 7.1 months (HR, 0.62; 95% CI, 0.28-1.36).

• Overall HER2-positive subgroup:

  • Objective response rate: 48.9% in the evorpacept group and 24.5% in the TRP group.

  • Median duration of response: 15.7 months and 9.1 months.

  • Median PFS: 7.5 months and 6.7 months (HR, 0.64; 95% CI, 0.39-1.07).

Adverse Effects and Safety

Adverse effects in the evorpacept group were similar to those in the control group, providing an acceptable safety profile.

• The most common severe (grade 3) adverse effects were:

  • Decreased neutrophil count: 19% in both groups.

  • Anemia: 22.2% in the evorpacept group and 17.5% in the control group.

  • Other common effects included decreased white blood cell count, hypertension, fatigue, and febrile neutropenia.

• Grade 4 adverse effects: Neutropenia (6.3% and 3.2%).

Treatment-Related Mortality

• 11 patients died during the study, and 2 deaths were considered treatment-related.

• One patient in the evorpacept group died from esophageal perforation, while one in the TRP group died from pneumopathy.

Commentary

These findings suggest that evorpacept is a promising option for patients with gastric/GEJ cancer, with an acceptable safety profile. They support further studies.

The data indicate that adding evorpacept to standard treatment for HER2-positive gastric and GEJ cancers may provide better response rates and longer responses through a new immunotherapy approach targeting CD47. This is an important development that could improve patients’ quality of life and survival.