María Díez Campelo, MD of the Universidad de Salamanca speaks about a Randomized phase 2 trial of pevonedistat plus azacitidine versus azacitidine for higher-risk MDS/CMML or low-blast AML.
Link to Abstract:
Pevonedistat is the first expressed, developmentally downregulated 8 (NEDD8)-activating enzyme (NAE) small-molecule neural precursor cell inhibitor; NAE promotes the conjugation of NEDD8, a small ubiquitin-like protein that activates Cullin-RING E3 ubiquitin ligases (CRLs)[4,5,6]. Pevonedistat inhibition of NAE prevents degradation of CRL substrates integral to tumor cell development, proliferation, and survival, leading to the death of cancer cells [4,5,6]. Pevonedistat + azacitidine demonstrated preclinical synergistic antitumor activity in xenografts of AML and was well tolerated with promising clinical activity in patients with untreated AML . This phase 2, multicenter, national, randomized, managed, open-label trial (NCT02610777) compared pevonedistat + azacitidine to single-agent azacitidine in patients with higher-risk MDS/CMML and LB-AML who had not previously received a hypomethylating agent based on these findings.
Adults with morphologically confirmed higher-risk MDS, non-proliferative CMML, or LB-AML (20-30 percent bone marrow myeloblasts) were enrolled in the study; these patients were eligible for enrolment because the diseases are part of the higher-risk MDS continuum and were included in the seminal randomized study showing substantial improvement in azacitidine overall survival (OS) versus azacitidine overall survival (OS) According to the updated international prognostic scoring system (IPSS-R), patients with MDS/CMML were required to have a very moderate, high or intermediate risk; patients with intermediate-risk IPSS-R (>3–4.5 points) had ~5 percent myeloblasts of the bone marrow (see Supplementary Appendix for detailed eligibility criteria).
Patients were randomized to receive either pevonedistat 20 mg/m2 (intravenous) on days 1/3/5 plus azacitidine 75 mg/m2 (intravenous or subcutaneous) on days 1-5/8/9 or azacitidine alone on the same schedule on days 1/3/5 plus azacitidine 75 mg/m2 (intravenous or subcutaneous) on days 1-5/8/9 or stratified to four categories: LB-AML and MDS/CMML with very high/high/intermediate IPSS-R risk. Treatment continued until unacceptable toxicity, relapse, transformation to AML (defined by World Health Organization classification as >20% blood or marrow blasts and 50% increase in baseline blast count), progressive disease (PD), or subsequent anti-cancer or hematopoietic SCT therapy is initiated. Patients with PD may continue care if clinical benefit is derived if their disease has not been converted to AML.
Initially, the study was driven by a primary event-free survival endpoint (EFS, described as the time from randomization to death or transformation to higher-risk MDS/CMML AML or LB-AML death). The primary endpoint was updated to OS, with EFS as a secondary endpoint, in consultation with regulatory agencies after completion of enrollment. The Supplementary Appendix lists other secondary and exploratory endpoints. The response assessment was based on the updated International Working Group (IWG) MDS requirements for higher-risk MDS/CMML patients and the revised IWG AML guidelines for LB-AML patients. Local bone marrow aspirate blast counts and transfusions and central laboratory results are based on disease evaluations. Toxicity was measured according to the Standard Terminology Requirements for Adverse Events of the National Cancer Institute, version 4.03. The Supplementary Appendix contains more descriptions of the evaluations and statistical analysis.