According to results from the phase 2 ASPEN-06 trial, the addition of evorpacept to trastuzumab, ramucirumab, and paclitaxel showed promising activity for patients with HER2-positive gastric or gastroesophageal junction (GEJ) cancers.

These results were first presented by Kohei Shitara, MD, National Cancer Center East, Kashiwa, Japan, at the 2025 American Society for Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium.

Dr Shitara explained, “Evorpacept is a differentiated CD47 blocker that works in combination to spare healthy cells and deliver cancer cells for macrophage destruction.” This agent is currently being evaluated in combination with anticancer antibodies and checkpoint inhibitors across cancer types.

The global, randomized, phase 2/3 APEN-06 trial enrolled patients with HER2-positive advanced or metastatic gastric/gastroesophageal cancers who had undergone 1 or 2 prior lines of therapy and had progressed on or after prior anti-HER2 therapy. There were 127 patients in the intention-to-treat population, with a subpopulation (n = 48) who had a fresh tumor tissue biopsy (median 1.1 month prior to study treatment dosing) following prior anti-HER2 treatment. Patients were randomized to either evorpacept 30 mg/kg twice a week plus trastuzumab, ramucirumab, and paclitaxel (evorpacept arm), or trastuzumab, ramucirumab, and paclitaxel (control arm). The primary objectives were an improvement of objective response rate (ORR) in the evorpacept arm compared to a historical ORR (30%) of ramucirumab and paclitaxel, and improvement of ORR in the evorpacept arm vs the internal control arm (represented by a delta of ≥ 10%), in both the intention-to-treat population and the subpopulation of patients with a more recent biopsy.

The ORR of the evorpacept arm was 41.3% vs 26.6% in the control arm. The difference between the ORR of the evorpacept arm and the historical ORR of ramucirumab and paclitaxel was not statistically significant (P = .095). However there was a meaningful delta of 14.7% when comparing the ORR of the evorpacept arm to that of the control arm (exploratory analysis, P = .028). The median duration of response was 15.7 months in the evorpacept arm and 9.1 months in the control arm. The median PFS was similar between both arms, however Dr Shitara stated, “the PFS curve showed a separation of the median favoring [the evorpacept arm], with a hazard ratio of 0.77.” Dr Shitara went on to explain that the response on the evorpacept arm was both deeper and more durable than that on the control arm, based on analyses of tumor size reduction and duration of response.

Within the prespecified population of patients with fresh HER2-positive biopsies (n = 48) the ORR of the evorpacept arm was 59.1% arm vs 23.1% in the control arm (delta, 36%; exploratory analysis, P = .004), and was favorable to the historical ORR of ramucirumab plus paclitaxel. A benefit was also seen in the PFS in this subgroup, with a median PFS of 9.5 months in the evorpacept arm vs 7.1 months in the control arm (HR, 0.62).

Treatment in the evorpacept arm was well tolerated with a safety profile consistent with prior evorpacept experience. Dr Shitara summarized, “the incidence of adverse events due to any cause was comparable by arm.” There were 2 grade 5 treatment-emergent adverse events deemed to be treatment related, 1 in the evorpacept arm due to esophageal perforation, and 1 in the control arm due to pneumopathy.

Dr Shitara concluded the addition of evorpacept to trastuzumab, ramucirumab, and paclitaxel resulted in an improved ORR and duration of response when compared to the control of trastuzumab, ramucirumab, and paclitaxel. He went on, “patients with confirmed HER2-positive expression via either fresh biopsy or ctDNA received the greatest benefit in ORR, DOR, and PFS, indicating that HER2-positive expression is a key biomarker and validating evorpacept [mechanism of action].” Dr Shitara added that “evorpacept [plus trastuzumab, ramucirumab, and paclitaxel] warrants further evaluation in [second- and third-line] patients with gastric/GEJ cancer.”

Source:

Shitara K, Wainberg ZA, Tabernero J, et al. 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). Presented at 2025 ASCO Gastrointestinal Cancers Symposium. January 23-25, 2025; San Francisco, CA. Abstract 332.