Phase I/Ⅱ study evaluating the safety and preliminary efficacy of amulirafusp alfa (IMM0306) in combination with lenalidomide in patients with relapsed/refractory CD20-positive follicular lymphoma

Abstract

Abstract Background: Follicular lymphoma (FL) is characterized by a relapsing and incurable course, wherein patients require multiple lines of therapy. Immunotherapy approaches, including an anti-CD20 monoclonal antibody (mAb) with alkylator-based chemotherapy, are preferred but remains need to improve durability and chemotherapy may have substantial toxicities. Amulirafusp alfa (IMM0306) consists of anti-CD20 mAb fused with the CD47 binding domain of signal regulatory protein α (SIRPα). It exerts potent anti-cancer efficacy by activating both macrophages and NK cells via blockading of CD47- SIRPα interaction and FcɣR engagement. Lenalidomide was approved for relapsed or refractory (R/R) indolent non-Hodgkin's lymphoma (iNHL). Here, we report efficacy results from a phase Ⅱ study and the safety data pooled from phase Ib and Ⅱ study of adding IMM0306 to lenalidomide in patients with R/R FL (NCT05771883). Methods: Patients with CD20-positive FL (grade 1-3a) and requiring treatment after ≥ 1 prior systemic therapy including an anti-CD20 mAb, were enrolled to receive amulirafusp alfa 1.6 mg/kg iv QW up to 2 years with lenalidomide 20 mg po QD Cycle 1 to 12 on Days 1 to 21 in each 28-day cycle. The primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), safety, and pharmacokinetics/ pharmacodynamics (PK/PD). Results: As of July 10, 2025, 38 patients with FL were enrolled in phase Ⅱ. Median age was 54 years (range, 32-74); 57.9% male; 42.1% intermediate- or high-risk FLIPI; 92.1% stage III-IV disease; and 26.3% with positive bone marrow involvement, 52.6% were refractory to prior anti-CD20 mA, defined as no response to or progression within 6 months of completion of the last dose of anti-CD20 mA therapy. The median number of prior line therapy was 1 (range, 1-5). At data cutoff, 9 patients (23.6%) had discontinued treatment, primarily due to disease progression (15.8%). Among 34 efficacy-evaluable patients, the complete response rate (CRR) and ORR were 67.6% and 91.2% respectively. With median follow-up of 9.02 months, the median PFS was not reached, and the PFS rate at 6 months was 91.2% (95% CI, 75.1-97.1). Among 18 CD20-refractory patients, the CRR, ORR and 6-month PFS rate were 66.7%, 88.9% and 88.9% (95% CI, 62.4-97.1), respectively. The safety-evaluable population included 47 FL patients, of whom 9 patients were in phase Ib and 38 patients were in phase Ⅱ. The most common treatment related adverse events (TRAEs) (≥ 20%) were neutrophil count decreased (80.9%), white blood cell (WBC) count decreased (76.6%), platelet count decreased (70.2%), anemia (59.6%), lymphocyte decreased (55.3%), blood bilirubin increased (31.9%), infusion-related reactions (34.0%), hypoalbuminaemia (23.4%), upper respiratory tract infection (23.4%), and asthenia (21.3%). Grade 3-4 TRAEs occurred in 44 (93.6%) patients, the most common Grade 3-4 TRAEs were neutrophil count decreased (61.7%), WBC decreased (42.6%), lymphocyte decreased (42.6%), and platelet count decreased (21.3%). 11 (23.4%) patients experienced serious TRAEs. Amulirafusp alfa dose reduction was required in 10 (21.3%) patients and lenalidomide dose reduction was required in 21 (44.7%) patients due to TRAEs. 2 (4.3%) patients experienced TRAE leading to the study drug discontinuation, one patient due to Type I hypersensitivity and one patient (discontinued lenalidomide only) due to rash, and both adverse events were resolved with sequelae or recovered to grade 1. No patient experienced TRAE leading to death. The population PK analysis indicated that a two-compartment model with parallel linear and non-linear elimination better described the pharmacokinetic characteristics of amulirafusp alfa, and exposure-response analysis demonstrated that higher amulirafusp alfa exposure was associated with higher ORR and CRR, as well as higher AE incidence. Conclusions: Amulirafusp alfa in combination with lenalidomide showed a high rate of response and a well-tolerated safety profile in patients with R/R FL. This phase Ib/Ⅱ study is still ongoing.