This study represents the first evaluation of Evorpacept combined with rituximab in relapsed/refractory non-Hodgkin lymphoma (NHL), demonstrating favorable tolerability without dose-limiting toxicities and significant clinical response rates, establishing the foundation for subsequent Phase II clinical investigations.
Literature Overview
This article titled 'Evorpacept plus rituximab for the treatment of relapsed or refractory non-Hodgkin lymphoma: results from the phase I ASPEN-01 study' published in Haematologica magazine reviews Phase I clinical trial results of Evorpacept (a novel high-affinity CD47-SIRPα fusion protein) combined with rituximab in patients with relapsed/refractory B-cell NHL (R/R NHL), assessing safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity.
Background Knowledge
CD47 is a transmembrane protein broadly expressed on normal cell surfaces that transmits 'don't eat me' signals through SIRPα binding on macrophages to inhibit phagocytosis. However, numerous hematological and solid tumors overexpress CD47, enabling immune escape from macrophage-mediated phagocytosis. Evorpacept is a novel high-affinity CD47-blocking fusion protein that enhances antibody-dependent cellular phagocytosis (ADCP) by inhibiting CD47-SIRPα signaling while incorporating a non-effector Fc domain to prevent non-specific phagocytosis of normal cells. Rituximab, a CD20-targeted therapeutic antibody used in B-cell lymphomas, has limited monotherapy efficacy particularly in relapsed/refractory patients. Preclinical data from this study demonstrated Evorpacept significantly enhances rituximab-mediated phagocytosis, improving antitumor effects. ASPEN-01 is a multicenter, open-label, dose-escalation and expansion Phase I trial evaluating Evorpacept monotherapy and combinations with pembrolizumab, rituximab, or trastuzumab for safety and preliminary antitumor activity. This analysis focuses on the R/R NHL cohort receiving Evorpacept-rituximab combination, providing initial evidence for clinical development.
Research Methods and Experiments
ASPEN-01 was conducted across 10 centers in the United States and South Korea, enrolling 33 R/R NHL patients: 22 received 10 mg/kg Evorpacept and 11 received 15 mg/kg. All patients received fixed-cycle rituximab therapy (375 mg/m² weekly for 4 weeks, followed by once every 4 weeks for 8 months). Primary endpoints were maximum tolerated dose (MTD) and dose-limiting toxicity (DLT), while secondary endpoints included safety, pharmacokinetics, overall objective response rate (ORR), duration of response, progression-free survival (PFS), and overall survival (OS). CD47 target occupancy and immune-related biomarkers were also evaluated.
Key Conclusions and Perspectives
Research Significance and Prospects
This Phase I study establishes clinical safety and preliminary efficacy of Evorpacept-rituximab combination in R/R NHL, supporting progression to Phase II evaluation. Evorpacept's unique molecular design enables effective CD47 blockade while preserving normal cell protection, thereby enhancing antibody-mediated phagocytosis. Future studies should explore combination regimens with immunotherapies or other targeted agents to optimize antitumor immune responses.
Conclusion
In conclusion, ASPEN-01 demonstrates that Evorpacept combined with rituximab achieves favorable safety and preliminary antitumor activity in R/R NHL patients, particularly showing enhanced efficacy in indolent subtypes. The combination achieves high target occupancy without significant hematologic toxicity, providing critical evidence for advancing clinical research. Subsequent trials will validate these findings in broader populations and identify predictive biomarkers to guide personalized treatment strategies.
