Updated Results from a Phase I Trial of Amulirafusp Alfa (IMM0306) in Patients with Relapsed or Refractory CD20-Positive B-Cell Non-Hodgkin's Lymphoma

Introduction: Amulirafusp alfa (IMM0306) is a fusion protein of CD20 monoclonal antibody (mAb) with the CD47 binding domain of SIRPα on both heavy chains. It exerts potent and robust cancer killing efficacy by activating both macrophages and NK cells via blockade of CD47-SIRPα interaction and FcɣR engagement. Here, we report the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) results of phase I trial in patients with relapsed or refractory (r/r) CD20-positive B-cell non-Hodgkin's lymphoma (B-NHL). Methods: Eligible patients with r/r CD20-positive B-NHL were enrolled in this open-label, multicenter phase I trial (NCT05805943). IMM0306 was administered as at escalating doses of 0.04, 0.1, 0.25, 0.5, 0.8, 1.2, 1.6, 2.0 mg/kg intravenously once a week after a 2-week single-dose observation period, until disease progression or intolerable toxicity. The primary objective is to evaluate the safety, tolerability, and to determine the recommended dose for Phase Ⅱ trial (RP2D). The secondary objective is to evaluate the preliminary efficacy, PK and the immunogenicity of IMM0306. Dose-limiting toxicity (DLT) was evaluated in the first 28 days. Safety was evaluated per CTCAE version 5.0, tumor assessments were performed every 8 weeks by Lugano 2014. Results: As of Apr 18, 2024, 48 patients were enrolled. The median age was 56 years old with 30 (62.5%) males. 33 (68.8%) patients had ECOG PS ≥ 1. The median number of prior lines of therapy was 3. All patients received previous anti-CD20 treatment. Among the 33 efficacy evaluable patients who received doses of 0.8-2.0 mg/kg, the overall response rate (ORR) was 30.3% (10/33), including 15.2% (5/33) complete response (CR) and 15.2% (5/33) partial response (PR); Among 17 efficacy evaluable patients with r/r follicular lymphoma (FL) who received doses 0.8-2.0 mg/kg, the ORR was 41.2% (7/17), including 23.5% (4/17) CR. The median progression free survival (PFS) assessed by investigator was 10.58 months with median follow-up of 11.53 months. The 9-month, 12-month, and 18-month PFS was 53.8%, 44.9% and 44.9%, respectively. The median duration of response (DoR) was not reached and the 26-week DoR rate among the 7 patients with objective response was 100%. No DLT was observed. The most frequent treatment related adverse events (TRAEs) (≥20%) were WBC decreased (66.7%), anemia (64.6%), lymphocyte decreased (60.4%), ANC decreased (47.9%), PLT decreased (47.9%) and infusion-related reactions (35.4%). Grade ≥ 3 TRAEs occurred in 33 (68.8%) patients, with the most common (≥10%) being lymphocyte decreased (58.3%), WBC decreased (20.8%), ANC decreased (18.8%) and anemia (10.4%). Six (12.5%) patients experienced treatment related serious adverse event. Discontinuation due to AEs occurred in 1 patient (grade 4 PLT decreased without bleeding occurred after DLT evaluation period). No AE led to death. IMM0306 exhibited non-linear PK characteristics across the dose range of 0.04 to 2.0 mg/kg and no apparent accumulation was observed after repeated dosing. Forty-six patients were included in the ADA analysis set, and only 2 (4.3%) patients were ADA positive after IMM0306 administration. No significant effects of ADA on PK, safety and efficacy were observed. At 1.2 mg/kg, CD47 receptor occupancy on peripheral lymphocytes was saturated, suggesting IMM0306 is well tolerated from perspective of CD47 engagement in high dose cohorts (1.2-2.0 mg/kg). B-cell counts depleted rapidly at doses 0.8-2.0 mg/kg. Elevated cytokines levels were observed after first dosing of IMM0306, but multiple dosing did not stimulate further cytokine activation. The RP2D was determined as 2.0 mg/kg based on the integrated evidence from safety, efficacy, PK and PD. Conclusions: IMM0306 demonstrated a manageable safety profile and a favorable anti-tumor activity for patients with r/r CD20-positive B-NHL, especially in patients with r/r FL.