Results from the ASPEN-06 phase 2 trial published in Nature Medicine on September 24 detail the effects of adding evorpacept to standard treatment for advanced gastric and gastroesophageal junction cancers, showing increased tumor response rates while overall survival remained comparable between study arms.
Understanding HER2 and Tumor Evolution in Advanced Gastric Cancer
Gastric cancer remains a significant clinical challenge globally, with roughly 20 percent of cases demonstrating overexpression of the HER2 protein, according to data outlined by the Italian Medicines Agency (AIFA). While initial therapies specifically target this receptor, tumors frequently mutate and alter their biological profile over time. Consequently, a protein level measured at the initial diagnosis may disappear or decline significantly by the time a patient requires subsequent lines of care, making repeated biopsies essential to confirm whether the therapeutic target is still present.
Trial Design and Findings for Evorpacept
The international ASPEN-06 trial evaluated 127 patients who had already progressed following prior anti-HER2 therapies. Researchers randomized participants to receive a baseline regimen of trastuzumab, ramucirumab, and paclitaxel, with one arm receiving the addition of the investigational drug evorpacept. Evorpacept targets CD47, a surface protein that binds to the SIRPα receptor and prevents macrophages from engulfing abnormal cells. By blocking this interaction, the therapy aims to enhance macrophage activity against cancer cells already flagged by anti-HER2 antibodies.
According to the findings published by K. Shitara and colleagues, objective tumor responses occurred in 40.3 percent of patients receiving evorpacept, compared to 26.6 percent in the control group. In patients whose repeat biopsies confirmed persistent HER2 expression, response rates reached 54.8 percent with evorpacept versus 23.1 percent without it.
Progression-Free Survival and Clinical Endpoints
Despite higher initial response rates, median progression-free survival—the duration patients lived without their disease worsening—measured 7.5 months in the evorpacept group and 7.4 months in the control group. Among patients who remained strictly HER2-positive at biopsy, progression-free survival reached 9.0 months versus 7.4 months. While responses lasted longer in the experimental arm at 15.7 months compared to 7.6 months, updated survival analyses showed that overall survival remained largely similar between cohorts.
Safety data indicated higher rates of hematological toxicities in the experimental arm, including neutropenia and anemia. Adverse events of grade 3 or higher affected 90.5 percent of patients receiving evorpacept, compared to 79.4 percent in the control group. The trial received funding from ALX Oncology, the manufacturer of evorpacept, which contributed to study design, data collection, and manuscript preparation.
Regulatory Context and Established Options
Treatment options for advanced HER2-positive gastric cancer continue to evolve alongside other regulatory milestones. In related treatment pathways, the antibody-drug conjugate trastuzumab deruxtecan secured reimbursement approval from AIFA as a monotherapy for adult patients with advanced gastric or gastroesophageal junction adenocarcinoma who previously received a trastuzumab-based regimen. Clinical trials such as DESTINY-Gastric01 and DESTINY-Gastric02 demonstrated significant improvements in objective response rates and overall survival for patients progressing past initial therapies, providing a vital benchmark for modern therapeutic efficacy in Western and Eastern patient populations alike.
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