Dose-dependent antitumor activity of HCB101 plus ramucirumab and paclitaxel in previously treated gastric cancer.

Abstract

372 Background: Patients with advanced gastric adenocarcinoma who progress after first-line (1L) therapy have limited options, with second-line (2L) response rates typically in the low teens. The CD47–SIRPα axis suppresses macrophage-mediated phagocytosis and enables tumor immune evasion. HCB101 is a next-generation SIRPα-Fc-fusion protein engineered to selectively block CD47 with minimal red blood cell blinding, restoring phagocytosis, and bridging to adaptive immunity. Ramucirumab normalizes tumor vasculature and reduces VEGF-driven immunosuppression, while paclitaxel promotes immunogenic cell death and antigen release. This triple regimen may integrate innate and adaptive immunity, vascular normalization, and chemotherapy-induced antigen release. Methods: HCB101-201 (NCT06771622) is an ongoing, multicenter, open-label, Phase Ib/IIa trial evaluating HCB101 plus ramucirumab and paclitaxel in advanced gastric adenocarcinoma in Mainland China. Eligible participants (≥18 years and progressed after 1L therapy) received escalating weekly doses of HCB101 (2.56-30 mg/kg) with ramucirumab (8 mg/kg, Days 1 and 15) and paclitaxel (80 mg/m2, Days 1, 8, and 15) in 28-day cycles. A 3+3 design evaluated dose-limiting toxicities (DLTs) and defined the recommended Phase 2 dose (RP2D). Part II will expand at RP2D. Primary endpoints were safety and tolerability; secondary endpoints included objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Exploratory endpoints assessed CD47 receptor occupancy and immune-related biomarkers. Results: As of Sept 05, 2025, 12 participants were treated at 2.56, 5.12, or 8.00 mg/kg. One DLT occurred at 8.00 mg/kg (Grade 4 thrombocytopenia) and recovered to Grade 2 within 10 days. The most frequent HCB101-related AEs were decreased white blood cell count (26 occurrences) and neutrophil count (17 occurrences), consistent with the chemotherapy background. At 2.56 mg/kg (n=4), all evaluable participants achieved stable disease (SD). At a 5.12 mg/kg dose (n=3), all evaluable participants achieved confirmed partial responses (PRs), with tumor shrinkage of 33%, 37%, and 46%. At an 8.00 mg/kg dose (n=5), two evaluable participants achieved confirmed PRs, with tumor shrinkage of 78% and 31%; 3 remain under evaluation. Conclusions: HCB101 combined with ramucirumab and paclitaxel demonstrated manageable safety and promising dose-dependent antitumor activity in 2L gastric cancer. While the 2.56 mg/kg dose showed disease stabilization, all evaluable participants in the 5.12 and 8.00 mg/kg cohorts achieved PRs, suggesting the presence of a therapeutic window. These early findings support continued investigation of HCB101 as a differentiated CD47-SIPRa therapy with potential to reprogram the gastric tumor microenvironment and improve outcomes for patients with previously treated advanced gastric cancer. Clinical trial information: NCT06771622 .