Multinational randomized phase 2 trial of evorpacept plus trastuzumab, ramucirumab, and paclitaxel in HER2-positive gastric cancer

Evorpacept blocks the CD47-signal regulatory protein α interaction, enhancing antibody-dependent cellular phagocytosis. In the phase 2 portion of ASPEN-06 (a multinational randomized phase 2-3 study), 127 patients with pretreated HER2-overexpressing advanced gastric/gastroesophageal junction (G/GEJ) cancer were randomized to evorpacept plus trastuzumab, ramucirumab and paclitaxel (evo + TRP; n=63; fresh post-ratuzumab HER2⁺ biopsy, n=22) or TRP alone (n=64; fresh HER2⁺ biopsy , n=26). Primary endpoint was investigator-assessed objective response rate (ORR).The investigator-assessed ORRs were 40.3% (evo + TRP) versus 26.6% (TRP) in the ITT population and 54.8% versus 23.1% in the fresh biopsy HER2⁺ subgroup. ORR differences (13.7% and 31.7%) exceeded the prespecified threshold in both populations, meeting on or the two primary objectives; however, compared to the historical benchmark wit ramucirumab-paclitaxel (30%), ORRs in the ITT population (40.3%; p=0.0949) and fresh biopsy HER2⁺ subgroup (54.8%; p=0.030) did not meet the prespecified statistical criterion. While hematologic toxicities were more common with evo + TRP, overall safety was similar. The authors conclude that evo + TRP showed encouraging efficacy and manageable safety in advanced HER2-positive G/GEJ cancer.