Abstract CT037: A phase I investigator-initiated trial of evorpacept (ALX148), lenalidomide and rituximab for patients with relapsed or refractory B-cell non-Hodgkin lymphoma
Authors: Strati Paolo , Feng Lei , Chihara Dai , Westin Jason , Ahmed Sairah , Fayad Luis , Henderson Jared , Davidson Jeffrey , McChesney Elizabeth , Nastoupil Loretta , Neelapu Sattva , Flowers Christopher 
Published: April 2024

Abstract
Introduction. We have recently demonstrated that pro-tumoral SIRPα+ macrophages may mediate 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. In a phase I trial including 33 pts with RR B-NHL it was well tolerated in combination with rituximab. We hypothesized that evorpacept and R2 will be synergistic, and the combination will be safe and effective for the treatment of pts with RR B-NHL.
Methods. This single arm phase I study (NCT05025800) was conducted between 11/2021 and 9/2023 (data cut-off 12/2023). Adult pts with RR B-NHL who had received at least 2 prior lines of systemic therapy (1 in case of indolent B-NHL [iNHL]) were included. Evorpacept was administered intravenously (IV), in a 28-day cycle, for 12 cycles, at two dose levels (DL): 30 mg/Kg on day (D) 1 and D15 (DL1), or 60 mg/Kg on day 1 (DL2); rituximab IV was given weekly during cycle 1, and on D1 during cycles 2-6; lenalidomide 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 criteria.
Results. Twenty pts were included in the study. Median age was 61 (27-85), 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; 20 (100%) had previously received an anti-CD20 monoclonal antibody, 13 (72%) chemoimmunotherapy, and 15/18 (83%) iNHL pts had intermediate-high FLIPI. Three pts were treated at DL1, 17 at DL2, and no DLT was observed. The most common grade 3-4 adverse events included: neutropenia (55%), infections (30%), ALT increase (15%), AST increase (10%), skin rash (10%), and anemia (10%). Eight (40%) pts experienced a cycle delay, mainly due to grade (G) 1 AST/ALT elevation; 6 (30%) required a dose reduction for lenalidomide, none for evorpacept; 1 pt discontinued treatment after 1 cycle due to G3 lenalidomide-associated myocarditis. Sixteen (80%) pts achieved CR and best overall response rate was 90%. After a median follow-up of 16 months (95% CI, 12-20 months), 1-year PFS rate was 70% and 1-year OS rate was 90%.
Conclusions. The combination of evorpacept and R2 is well tolerated in pts with RR B-NHL, with similar toxicity and promising anti-tumoral activity as compared to historical CR rates with R2 alone (34%). Bulk RNA sequencing and multiplex immunofluorescence are being performed on tissue biopsies collected before and during treatment, to characterize its effects on the tumor immune microenvironment. A phase 2 study investigating its efficacy in pts with previously untreated iNHL is now enrolling.
Citation Format: Paolo Strati, Lei Feng, Dai Chihara, Jason Westin, Sairah Ahmed, Luis Fayad, Jared Henderson, Jeffrey Davidson, Elizabeth McChesney, Loretta Nastoupil, Sattva Neelapu, Christopher Flowers. A phase I investigator-initiated trial of evorpacept (ALX148), lenalidomide and rituximab for patients with relapsed or refractory B-cell non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT037.