Abstract LB369: Final results of a phase I trial of evorpacept (ALX148), lenalidomide, and rituximab for patients with B-cell non-Hodgkin lymphoma

Abstract Introduction: Increase in pro-tumoral SIRPα+ macrophages has been described as a mechanism of resistance to lenalidomide and rituximab (R2) in patients (pts) with relapsed or refractory (RR) B-cell non-Hodgkin lymphoma (B-NHL). Evorpacept (ALX148) is a novel high-affinity CD47 blocker that abrogates the ‘do-not-eat-me signal’ provided to SIRPα+ macrophages. We hypothesized that the combination of evorpacept and R2 will be safe and effective for pts with RR B-NHL. Methods: This single arm phase I study (NCT05025800) was conducted between 11/2021 and 9/2023 (data cut-off 01/2025). Adult pts with RR B-NHL who had received at least 2 prior lines of systemic therapy (1 line in case of indolent B-NHL [iNHL]) were included. Evorpacept was administered intravenously (IV), in a 28-day cycle, until progression (or for 12 cycles in case of CR), 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. Dose limiting toxicity (DLT) was evaluated according to CTCAE v5 during cycle 1 and a Bayesian Optimal Interval design was used, with a target DLT rate of 0.3. Response was assessed according to Lugano 2014. Single-cell RNA sequencing was performed on tumor biopsies collected before treatment and during cycle 1. Results: Twenty pts were included in the study. Median age was 61 (27-85) years, 10 (50%) were male, and 7 (35%) were non-white; 15 (75%) had follicular lymphoma, 3 (15%) marginal zone lymphoma, 1 (5%) mantle cell lymphoma, and 1 (5%) Richter Syndrome; all had previously received an anti-CD20 monoclonal antibody, 13 (72%) chemoimmunotherapy, and 16 (80%) had progressed within 24 months. Three pts were treated at DL1, 17 at DL2, and no DLT was observed. The most common grade 3-4 adverse events included: neutropenia (60%), infections (30%), and ALT increase (15%). Sixteen (80%) pts achieved CR and best overall response rate was 90%. After a median follow-up of 28 months (95% CI, 18-28 months), 2-year PFS rate was 69% and 2-year OS rate was 84%. Serial tumor tissue samples were successfully sequenced in 16 patients. During treatment, a significant decrease in B cells, and a significant increase in T cells and macrophages was observed. In macrophages, pathways associated with cytokines, innate immune system, TLR signaling, endocytosis, phagocytosis, extracellular matrix interactions, and antigen presentation were upregulated. Conclusions: The combination of evorpacept and R2 has a safe toxicity profile, promising anti-tumoral activity (historical CR rate 30%), and induces favorable biological effects on multiple components of the tumoral immune microenvironment. A phase 2 study investigating its efficacy in pts with previously untreated and high tumor burden iNHL has completed enrollment. Citation Format: Tony Z. Zhuang, Lei Feng, Andrey Tyshevich, Darya Shavronskaya, Julia Alesse, Noel English, Lizzie Sheehan, Nikita Syzrantsev, Alexander Nesmelov, Dai Chihara, Jason Westin, Sairah Ahmed, Luis Fayad, Jared Henderson, Kylie Dent, Elizabeth McChesney, Sattva Neelapu, Christopher R. Flowers, Paolo Strati. Final results of a phase I trial of evorpacept (ALX148), lenalidomide, and rituximab for patients with B-cell non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB369.