Mikkael A. Sekeres, MD from Sylvester Comprehensive Cancer Center, University of Miami speaks about the ASH 2021 Abstract – 242 Pevonedistat (PEV) + Azacitidine (AZA) Versus AZA Alone As First-Line Treatment for Patients with Higher-Risk Myelodysplastic Syndromes (MDS)/Chronic Myelomonocytic Leukemia (CMML) or Acute Myeloid Leukemia (AML) with 20–30% Marrow Blasts: The Randomized Phase 3 PANTHER Trial (NCT03268954).
Link to Abstract:
https://ash.confex.com/ash/2021/webprogram/Paper146154.html
Background:
Single-agent hypomethylating agent (HMA) therapy is often used in older patients with higher-risk MDS/CMML or AML with 20–30 percent marrow blasts. The median response duration and survival for these individuals is poor, and many MDS patients progress to secondary AML, which has a very terrible prognosis. Novel HMA-based combination therapies are needed to improve survival, postpone AML transformation, and boost depth and duration of response compared to single-agent HMA therapy without extra toxicity or myelosuppression. In a randomized, proof-of-concept phase 2 study PEV – a first-in-class, selective inhibitor of NEDD8-activating enzyme – in combination with AZA demonstrated encouraging clinical efficacy vs AZA alone in patients with higher-risk MDS and AML with 20–30 percent marrow blasts, with nearly double the complete remission rate, almost triple the duration of response, and improved event-free survival (EFS) among patients with higher-risk MDS (Sekeres Leukemia 2021). (Sekeres Leukemia 2021). Without increasing myelosuppression, PEV + AZA exhibited a similar safety profile to AZA alone. The study design and patient characteristics from PANTHER, a worldwide, multicenter, randomized phase 3 trial, are presented in this paper (NCT03268954).
Methods:
Patients aged 18 years old who had a confirmed diagnosis of higher-risk MDS or higher-risk CMML (Revised International Prognostic Scoring System [IPSS-R] risk score >3; 5% marrow blasts for intermediate-risk patients) or AML with 20–30 percent marrow blasts and were chemotherapy/HMA-naive and ineligible for upfront intensive chemotherapy and/or allogeneic stem cell transplantation were randomized 1:1 to receive PEV 20 mg Patients were divided into four groups: very high, high, and intermediate risk MDS/CMML, as well as AML with 20–30 percent marrow blasts (by IPSS-R). The primary outcome was EFS, which was defined as the time from randomization to death or transformation to AML in patients with higher-risk MDS or CMML, or death in patients with AML. The operating system was an important secondary endpoint. Separate hierarchical testing procedures (total 1-sided alpha of 0.025 for each process) are being used to test EFS and OS in the higher-risk MDS cohort and the intent-to-treat (ITT) population, with OS testing in the AML cohort following.
Results:
A total of 454 patients, 324 with higher-risk MDS (n=161; n=163), 103 with AML (n=50; n=53), and 27 with higher-risk CMML (n=16; n=11), were randomized (PEV + AZA, n=227; AZA alone, n=227). The demographics and disease features at the start of the study were very evenly distributed between the two groups. In the ITT population, 58 percent of patients in the PEV + AZA and 63 percent of patients in the AZA alone arms were male, 91 percent and 86 percent were 65 years old (41 percent and 48 percent were 75 years old), and 89 percent /10 percent and 84 percent /15 percent had an Eastern Cooperative Oncology Group performance status of 0 or 1/2, respectively. IPSS-R risk group was very high in 39 percent and 36 percent of patients with higher-risk MDS who were treated with PEV + AZA or AZA alone, high in 37 percent and 39 percent, and intermediate in 24 percent and 25 percent; 93 percent and 94 percent of patients had de novo illness. According to European LeukemiaNet 2017 standards, 60 percent and 70% of patients with AML treated with PEV + AZA or AZA alone were classed as adverse-risk, respectively; 62 percent and 49 percent had de novo illness. There have been no new safety signals discovered to yet. Approximately 202 OS events had occurred at the predetermined second interim analysis for the primary endpoint of EFS (n=147 occurrences, higher-risk MDS).
Conclusions:
Patient characteristics were well-balanced between arms, and the sample is reflective of typical patients with higher-risk MDS/CMML and AML with 20–30 percent marrow blasts. EFS and OS will be presented for each treatment arm in the ITT population and the higher-risk MDS cohort, as well as data on secondary endpoints such as response rates and duration of response, time to AML transformation in patients with higher-risk MDS, rates of transfusion independence, and safety. If the outcomes are fulfilled, this will be the first phase 3 study in this scenario to show that adding a new drug to AZA improves efficacy.