Nicholas J. Short, MD Assistant Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center speaks about the ASH 2020 abstract 988 A Randomized Phase 2 Study of Pevonedistat, Venetoclax, and Azacitidine Versus Venetoclax Plus Azacitidine in Adults with Newly Diagnosed Acute Myeloid Leukemia (AML) Who Are Unfit for Intensive Chemotherapy.
Context
Pevonedistat is the first small-molecule, developmentally downregulated protein 8 (NEDD8)-activating enzyme-activating neural precursor cell inhibitor to be expressed (NAE). Inhibiting NAE inhibits the ubiquitination upstream of the proteasome of select proteins. Pevonedistat therapy disrupts the progression of the cell cycle and cell survival, leading to cell death in cancers, including myeloid malignancies. Pevonedistat in combination with azacitidine (AZA) was tolerable and demonstrated clinical activity in a phase 1b study in patients aged 60 years and older with untreated AML (Swords et al. Blood 2018). In a randomized phase 2 study of pevonedistat+AZA vs. AZA alone, pevonedistat+AZA improved event-free survival (EFS) and overall survival (OS) in patients with higher-risk myelodysplastic syndromes/chronic myelomonocytic leukemia and low-blast AML, had a comparable safety profile to AZA alone, did not increase myelosuppression, and retained AZA dose intensity (Adès et al. ASCO 2020). Venetoclax (VEN) is a small-molecule B-cell lymphoma 2 inhibitor that is approved in the United States for the treatment of patients with AML in combination with low-dose cytarabine or hypomethylating agents. It has been shown that VEN + AZA enhances OS vs. AZA alone and the combination for older patients with newly diagnosed AML who are unfit for standard intensive chemotherapy is emerging as a standard of treatment. Outcomes for these patients remain low despite recent advances; novel therapies are required that improve duration of response (DOR) or reduce relapse rates. Synergistic cytotoxic effects in AML cell lines and primary clinical AML samples were demonstrated by Pevonedistat in combination with VEN (Knorr et al. Cell Death Differ 2015). This is possibly mediated by pevonedistat-induced neutralization of prosurvival proteins, including protein differentiation of myeloid leukemia cells (MCL-1). A primary mode of resistance to VEN is thought to be the Upregulation of MCL-1. Treatment with pevonedistat + VEN can therefore help to prevent or resolve VEN resistance and to prolong DOR. The clinical benefit reported for both pevonedistat + AZA and VEN + AZA in AML and the preclinical evidence of synergy between pevonedistat and VEN indicate that combination therapy with all 3 therapies can lead to improved outcomes in patients with newly diagnosed AML who are unfit for intensive chemotherapy compared with VEN + AZA. The phase 1/2 triplet combination studies of pevonedistat, VEN, and AZA in secondary AML established the recommended phase 2 dose and showed a high response rate in this relatively refractory population (Short et al. EHA 2020).
Methodology
NCT04266795 is a phase 2 randomized, open-label, controlled study (Figure) that is being performed globally across ~85 sites. Eligible patients are those aged 18 years or older with morphologically confirmed newly diagnosed AML (2008 World Health Organization criteria) and deemed unfit due to age and/or comorbidity for treatment with cytarabine and anthracycline induction. Patients are randomized 1:1 to obtain an intravenous (IV) combination of pevonedistat 20 mg/m2 on days 1, 3, and 5, VEN 400 mg by mouth on days 1-28 in cycle 1 (ramp-up a schedule of 100 mg on day 1, 200 mg on day 2, 400 mg on days 3-28) and then on days 1-28 (days 1-21 if recovery is confirmed; will return to 28-day dosing if well tolerated) in cycle 2, and AZA 75 mg/m2 (IV or sub-28 if remission is confirmed) Randomization is stratified by age and subtype of AML (18-<75 years vs <75 years) (de novo vs secondary). EFS is the main endpoint (time from randomization to relapse from complete remission [CR] or CR with incomplete blood count recovery [CRi], treatment failure, or death from any cause, whichever occurs first). Secondary endpoints include OS; 6-month, 1-year, and 2-year OS; 30-day and 60-day mortality; CR rate; post-cycle 6 EFS; DOR; time to first response; time to relapse from CR/CRi or death; quality of life associated with health; pharmacokinetics; independence of red blood cell and platelet transfusion rate; and hospitalization rate. For detectable residual disease and mechanism of action studies, molecular characterization of bone marrow aspirates will be conducted. Leukemic stem cell removal and predictive response biomarkers will be evaluated. The research is expected to enroll ~150 patients; there is an ongoing recruitment.