Phase 2 Study of Pevonedistat plus Azacitidine versus Azacitidine in Patients with Higher-Risk Myelodysplastic Syndromes (MDS)/Chronic Myelomonocytic Leukemia (CMML) or Low-Blast Acute Myelogenous Leukemia (LB-AML) (NCT02610777): Subset Analysis in Higher-Risk MDS

Context: Pevonedistat, the first small-molecule inhibitor of NEDD8-activating enzyme, disrupts proteasomal degradation of select proteins. Setting: Patients with higher-risk MDS/CMML (IPSS-R >3, including intermediate [≥5% blasts], high, or very high risk) or LB-AML naive to hypomethylating agents were randomized 1:1 to receive intravenous pevonedistat 20 mg/m2 on days 1, 3, and 5 plus intravenous/subcutaneous azacitidine 75 mg/m2 on days 1–5, 8, and 9 (n=58), or azacitidine alone (n=62), in 28-day cycles. This abstract focuses on the higher-risk MDS subgroup. Main outcome measures: The study was powered on an endpoint of event-free survival (EFS). Overall survival (OS), overall response rate (ORR) and safety were also assessed. Patient-reported health-related quality of life (HRQoL) was evaluated using the European Organization for Research and Treatment of Cancer (EORTC) QoL Questionnaire-C30. Mutational profiling was performed on screening bone marrow aspirate samples. Results: In the intent-to-treat (ITT) population (n=120), EFS trended longer (median, 21.0 vs 16.6 months; hazard ratio [HR]=0.67; 95% CI, 0.42–1.05; P=.076) and median OS was 21.8 vs 19.0 months (HR=0.80; 95% CI, 0.51–1.26; P=.334) with pevonedistat+azacitidine vs azacitidine. In patients with higher-risk MDS (n=67), EFS was longer (median, 20.2 vs 14.8 months; HR=0.54; 95% CI, 0.29–1.00; P=0.045) and median OS was 23.9 vs 19.1 months (HR=0.70; 95% CI, 0.39–1.27; P=0.240) with pevonedistat+azacitidine vs azacitidine. In response-evaluable patients with higher-risk MDS (n=59), ORR was 79% (pevonedistat+azacitidine) vs 57% (azacitidine); median duration of response was 34.6 vs 13.1 months, respectively. Median azacitidine dose intensity was 98% (both arms) in patients with higher-risk MDS. With pevonedistat+azacitidine vs azacitidine, 94% vs 83% of patients with higher-risk MDS had grade ≥3 adverse events (most common: neutropenia [38% vs 37%], febrile neutropenia [22% vs 31%]). No difference was observed in patient-reported HRQoL between arms, with similar mean scores maintained from study entry to end of treatment. Clinical activity was observed with pevonedistat+azacitidine in patients with higher-risk MDS harboring poor prognostic mutations. Conclusions: Pevonedistat+azacitidine led to longer EFS vs azacitidine in higher-risk MDS, had a comparable safety profile to azacitidine alone, and azacitidine dose intensity was maintained. A randomized phase 3 trial ( NCT03268954 ) is ongoing.