Editor's Note: The 2025 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI 2025) successfully concluded on January 25. During the conference, numerous high-impact research findings were presented, including the ASPEN-06 study (Abstract #332), a global Phase II/III randomized trial evaluating the efficacy of evorpact (Evo) in combination with trastuzumab, ramucirumab, and paclitaxel (TRP) in patients with HER2-positive gastric and esophageal cancer who had previously received anti-HER2 therapy but experienced disease progression. At the conference, a reporter from Oncology Frontier had the opportunity to conduct an exclusive interview with Dr. Kohei Shitara from the National Cancer Center Hospital in Japan regarding this study. The following is a summary of the discussion.

Study title：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)

Oncology Frontier: Congratulations on your abstract being selected for an oral presentation at this year’s ASCO GI conference. Could you briefly introduce the background and rationale behind the ASPEN-06 study?

Kohei Shitara: The ASPEN-06 study is a global Phase II/III randomized trial designed to evaluate the efficacy of evorpact (Evo) in combination with trastuzumab, ramucirumab, and paclitaxel (TRP) in patients with HER2-positive gastric and esophageal cancer who had previously received anti-HER2 treatment but experienced disease progression. Evorpacept is a CD47 blocker that enhances antibody-dependent phagocytosis, thereby boosting the efficacy of monoclonal antibodies such as trastuzumab. Prior studies have shown that Evo reduces hematologic toxicity, including cytopenia.

In this trial, patients were randomly assigned to either the Evo-TRP group or the TRP-alone group. The primary endpoint was the objective response rate (ORR). Among the 127 patients enrolled, approximately 40% underwent tissue biopsy to confirm HER2 status, while 65% were confirmed HER2-positive through circulating tumor DNA (ctDNA) analysis. The response rate in the Evo-TRP group was 40.3%, compared to 26.6% in the TRP-alone group. Although the improvement in ORR did not reach statistical significance when compared to historical controls (30% ORR for the combination of pembrolizumab and ramucirumab), the results still demonstrate the potential efficacy of Evo.

The response rate in the Evo-TRP group was more than 10% higher than in the TRP-alone group, and there was also a trend toward improved duration of response and progression-free survival (PFS). Notably, Evo showed the greatest efficacy in patients whose HER2 status was confirmed either through tissue biopsy or ctDNA analysis.

In terms of safety, there was no significant increase in toxicity. While a slightly higher incidence of neutropenia and anemia was observed in the Evo-TRP group, the difference was minimal, and there was no increase in febrile neutropenia. Overall, the findings from this trial indicate that the Evo-TRP regimen demonstrates promising anti-tumor activity in the treatment of HER2-positive gastric and gastroesophageal cancer.

Oncology Frontier: Could you share your plans for future research?

Kohei Shitara: The ASPEN-06 study is a Phase II/III trial, so the next step will be moving forward with a Phase III study. We are currently discussing various potential study designs. I believe that as we transition to a Phase III trial, it would be reasonable to recruit patients whose HER2-positive status has been confirmed through tissue biopsy. However, further discussions with the research team and regulatory agencies are needed before finalizing the study plan.

Additionally, this study highlights the potential of CD47 blockade in solid tumors. It may be the first trial to demonstrate such potential, not only for HER2 but also for other targets that can be addressed with monoclonal antibodies. Evo could also be combined with rituximab or other therapeutic agents, opening up further research opportunities and potential applications for this approach.