PF-08046040 (SEA-CD70), a Nonfucosylated CD70-Directed Antibody, in Combination with Azacitidine for Patients with Myelodysplastic Syndromes (MDS): A Phase 1 Dose-Finding and Dose Expansion Study
Authors: Grieselhuber Nicole R. , Baratam Praneeth , Advani Anjali S. , Yacoub Abdulraheem , Stevens Don A. , Aribi Ahmed , Tomlinson Ben K. , Yang Jay , Vachhani Pankit , Jurcic Joseph G , Oliai Caspian H. , Liegel Jessica , Pearson Edward , Rhenen Anna Van , Rotta Marcello , Rathi Kapil , Pinelli Juan , Chen Tara , Fathi Amir T. 
Published: December 2024

Introduction
PF-08046040 (SEA-CD70) is a humanized, nonfucosylated, CD70-directed IgG1 monoclonal antibody (Ab) with enhanced effector functions under development for treatment of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). CD70 is expressed on myeloid blasts in myeloid malignancies and is a potential target. SEA-CD70's proposed mechanisms of action include eliminating CD70+ cells via enhanced Ab-dependent cellular cytotoxicity, Ab-dependent cellular phagocytosis, and mediation of complement-dependent cytotoxicity. It also blocks interaction of CD70 with CD27, whose signal promotes stemness and proliferation of leukemic blasts. Preclinical studies showed additive activity of SEA-CD70 in combination with azacitidine (AZA), which is known to increase CD70 expression. The study's aim is to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of SEA-CD70 monotherapy and SEA-CD70 + AZA in patients (pts) with MDS.
Methods
This is a 6-part, Phase 1, open-label, multicenter, dose-finding and dose expansion study (NCT04227847). Here, we report findings in pts with previously untreated higher-risk (HR) MDS in Part D (dose optimization for combination of SEA-CD70 + AZA). Eligible pts were aged ≥18 years with treatment-naïve HR-MDS (Intermediate-2 or High risk per International Prognostic Scoring System [IPSS]), increased blasts (5-19%), and Eastern Cooperative Oncology Group performance status (ECOG PS) of ≤2. Pts were also categorized by revised IPSS (IPSS-R; Moderate High, High, or Very High). Pts received intravenous (IV) SEA-CD70 at 10 mg/kg or 20 mg/kg on D1 and D15 and subcutaneous/IV AZA 75 mg/m2 on D1-D7 of 28-day cycles.
Results
At data cutoff, June 9, 2024, 35 pts were enrolled, and 32 received ≥1 dose of SEA-CD70 (10 mg/kg, n = 14; 20 mg/kg, n = 18) + AZA. Median age was 72 y (range, 60-82). At baseline, most pts had an ECOG PS of 0-1 (84%) and High or Very High IPSS-R category (78%). Total median duration of SEA-CD70 + AZA treatment was 9.6 wks (range, 2-80); 44% of pts were receiving treatment at data cut-off. Most common (≥25%) treatment-emergent adverse events (TEAEs) were constipation (50%), diarrhea (31%), fatigue (25%), and thrombocytopenia (25%); infusion related reactions occurred in 16% of pts. Most common Grade ≥3 TEAEs were anemia, neutropenia, and thrombocytopenia (19% each). Most common reasons for permanent treatment discontinuation were progressive disease (20%), patient decision (14%), and AE (11%). For pharmacokinetics, SEA-CD70 plasma concentrations increased dose proportionally from 10 mg/kg to 20 mg/kg. There were 25 efficacy evaluable pts (10 mg/kg, n = 12; 20 mg/kg, n = 13). Objective response rate, defined by a modified 2006 International Working Group response criteria as the proportion of pts who achieved a best response of complete remission (CR), CR with partial hematologic recovery (CRh), or partial remission, was 42% (95% CI 15.2-72.3) for 10 mg/kg, 46% (95% CI 19.2-74.9) for 20 mg/kg, and 44% (95% CI, 24.4-65.1) overall. Blast clearance rate, defined as the proportion of pts who achieved a best response of CR, CRh or marrow CR, was 58% (95% CI 27.7-84.8) for 10 mg/kg, 54% (95% CI 25.1-80.8) for 20 mg/kg and 56% (95% CI, 34.9-75.6) overall. For the responders, median time to response (TTR) was 3.7 mo (range 1.6-3.8) for 10 mg/kg, 1.6 mo (range 0.7-1.7) for 20 mg/kg and 1.6 mo (range, 0.7-3.8) overall. Across both dose cohorts, median duration of response (DOR) was 13.6 mo (95% CI, 3.7-NE), median event-free survival (EFS) was 8.1 mo (95% CI, 2.1-NE), and median overall survival (OS) was 19.6 mo (95% CI, 8.1-NE). Of note, at data cut-off, OS/EFS/DOR data are not mature. The rate of conversion to transfusion independence was 36% (95% CI, 18.0-57.5), and the rate of transfusion independence maintenance was 28% (95% CI, 12.1-49.4). Following treatment, 5 (16%) pts received stem cell transplant; 3 immediately after and 2 pts received intervening anticancer therapy.
Conclusion s
SEA-CD70 appears to be well tolerated at 10 mg/kg and 20 mg/kg in combination with AZA. Overall, AEs were manageable, and there were no treatment-related or treatment-emergent dose reductions. Preliminary efficacy was observed for pts with HR-MDS, with 16% of pts subsequently receiving transplant for both 10 mg/kg and 20 mg/kg dose cohorts. Results support the continued development of SEA-CD70 + AZA for pts with myeloid malignancies.