A Phase I Trial of Evorpacept, Lenalidomide and Rituximab for Patients with B-cell Non-Hodgkin Lymphoma.

INTRODUCTION: SIRPα+ macrophages can mediate resistance to lenalidomide and rituximab (R2) in patients with B-cell non-Hodgkin lymphoma (B-NHL). Evorpacept (ALX148) is a novel CD47 blocker that abrogates interactions between lymphoma cells and SIRPα+ macrophages. METHODS: Adult patients with B-NHL who had received at least 2 prior lines of systemic therapy were included in this single arm phase I study (NCT05025800). Evorpacept was administered intravenously (IV), in a 28-day cycle, until progression, at two dose levels (DL): 30 mg/Kg on day (D) 1 and D15 (DL1), or 60 mg/Kg on day 1 (DL2); rituximab 375 mg/m2 IV was given weekly during cycle 1, and on D1 during cycles 2-6; lenalidomide 20 mg was given orally on D1-21 during cycles 1-6. Single-cell RNA sequencing was performed on tumor biopsies collected before treatment and during cycle 1. RESULTS: Twenty patients were included in this study. Median age was 61 (27-85) years and 18 (90%) had indolent B-NHL. Three patients were treated at DL1, 17 at DL2, and no dose limiting toxicity was observed. The most common grade 3-4 adverse events included: neutropenia (60%), infections (30%), and alanine transferase increase (15%). Sixteen (80%) patients achieved complete response and after a median follow-up of 28 months 2-year progression-free survival rate was 69%. During treatment, a significant increase in T cells and macrophages was observed, and macrophages pathways associated with anti-tumoral activity were upregulated. CONCLUSIONS: ER2 has a safe toxicity profile, promising anti-tumoral activity, and induces favorable biological effects on the tumoral immune microenvironment.