Pelabresib (CPI-0610) Combined with Ruxolitinib for JAK Inhibitor Treatment-Naïve Patients with Myelofibrosis: Durability of Response and Safety Beyond Week 24

Abstract

Background: Myelofibrosis (MF) is characterized by progressive bone marrow (BM) fibrosis, splenomegaly and cytopenias resulting from aberrant megakaryopoiesis and proinflammatory cytokine expression. These processes are heavily regulated by bromodomain and extraterminal domain (BET) protein-mediated gene expression (eg NF-κB target genes, MYC and BCL-2) and lead to myeloproliferation and cytopenias. The current standard of care for patients (pts) with MF is the Janus kinase inhibitor (JAKi) ruxolitinib (RUX); however, the depth and durability of responses, along with the percentage of pts that achieve ≥35% spleen volume reduction from baseline (BL; SVR35) and ≥50% total symptom score reduction (TSS) from BL (TSS50) with RUX monotherapy are limited. Pelabresib (CPI-0610; PELA) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB signaling and other relevant genes involved in MF disease pathways (Mascarenhas J, et al. HemaSphere 2022;6:99-100). In the ongoing Phase 2 MANIFEST study (NCT02158858), PELA is under investigation as monotherapy and in combination with RUX in pts with MF. Here, we present results from Arm 3 of MANIFEST (in which JAKi-naïve pts with MF receive PELA in combination with RUX). Aims: The primary endpoint of MANIFEST Arm 3 is SVR35 after 24 weeks (wks) of treatment. Secondary endpoints include TSS50, duration of splenic response, pharmacokinetics and safety. Exploratory endpoints include transfusion independence and changes from BL in BM fibrosis. In this abstract we will discuss results from the September 2021 data cut; longer-term data from the July 2022 data cut will be presented. Methods: Spleen volume was assessed by computed tomography or magnetic resonance imaging every 12 wks; TSS per Myelofibrosis Symptom Assessment Form v4.0; and BM fibrosis by biopsies at Wk 24 and Wk 48. Duration of splenic response and safety data are also evaluated. Data presented are from the September 2021 data cut; a more mature data set will be presented at the conference. Results: Eighty-four pts received ≥1 dose of PELA and RUX. Median age was 68 years (range 37-85); 24%, 61% and 16% had Dynamic International Prognostic Scoring System intermediate-1, intermediate-2 or high risk, respectively. Pts who did not reach Wk 24 were counted as nonresponders. At Wk 24 and Wk 48, 68% (57/84) and 60% (47/79) of pts, respectively, achieved SVR35. SVR35 at any time was achieved by 80% pts (67/84), and 87% (58/67) pts with SVR35 maintained response at the time of data cutoff. Median spleen volume change was -50% (range -84.4% to 27.9%) at Wk 24. Median time to SVR35 response was 12 wks (first on-treatment assessment of splenic response); durable spleen volume reductions were observed as depicted in mean spleen volume change over time in Figure 1. TSS50 was achieved by 56% (46/82) pts at Wk 24 and 43% (34/79) at Wk 48. TSS50 at any time was achieved by 81% pts (68/84). The median change in TSS was −59% (range −100% to 225%) at Wk 24. Mean TSS change over time is shown in Figure 2, indicating sustained reduction in symptom burden. Median follow up for Arm 3 was 21.8 (range 21.2-22.5) months; median treatment duration was not reached as of data cutoff. BM fibrosis improved by ≥1 grade in 28% (16/57) of evaluable pts at Wk 24 as assessed by central pathology review; 56% maintained the improvement at the next available assessment (Wk 48 or beyond) or longer; and 40% achieved ≥1 grade improvement at any time (best response). The most common hematologic treatment-emergent adverse event (TEAE) of any grade was thrombocytopenia, reported in 52% (Grade ≥3: 12%) of pts. Anemia was reported in 42% (Grade ≥3: 34%). Serious adverse events reported in ≥2 pts were respiratory tract infections (6 pts), pyrexia (3 pts) and anemia, multiorgan failure, fall and pelvic fracture (2 pts each). TEAEs that led to PELA discontinuation occurred in 7 pts (8%). Updated data with longer follow-up, including durability of splenic response and safety data from a more mature data set, will be available for presentation at the conference. Conclusions: The combination of PELA and RUX in JAKi-naïve pts with MF showed durable improvements in spleen volume, total symptom score and BM fibrosis, and was generally well tolerated. The randomized, double-blind, active-controlled Phase 3 MANIFEST-2 study is open for enrollment and evaluating the safety and efficacy of PELA in combination with RUX in JAKi treatment-naïve pts with MF (NCT04603495). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal