MDS-344: Pevonedistat Plus Azacitidine vs Azacitidine Alone in Higher-Risk Myelodysplastic Syndromes (MDS): Efficacy and Safety Results from Study P-2001 (NCT02610777)

Introduction: Pevonedistat, an investigational, first-in-class NEDD8-activating enzyme inhibitor, disrupts protein homeostasis, leading to cancer cell death. For patients with higher-risk MDS ineligible for transplant, real-world data reveal median overall survival (OS) is 11–15 months with treatment, yet no novel treatments have been approved in a decade. Methods: Patients with higher-risk MDS/chronic myelomonocytic leukemia or low-blast acute myeloid leukemia (AML) naive to hypomethylating agents were randomized 1:1, receiving pevonedistat (20 mg/m2 intravenously [IV], days 1, 3, 5) + azacitidine (75 mg/m2 IV/subcutaneously, days 1–5, 8, 9) (n=58) or azacitidine alone (n=62) in 28-day cycles until unacceptable toxicity, relapse, AML transformation, or progression. The study was powered for event-free survival (EFS: time from randomization to death/AML transformation, whichever occurred first). This report focuses on higher-risk MDS, including their cytogenetic and genetic characterization. Results: In patients with higher-risk MDS (n=67/120), baseline characteristics were balanced between arms. EFS was longer with pevonedistat+azacitidine vs azacitidine (median 20.2 vs 14.8 months; HR 0.54; 95% CI 0.29–1.00; p=.045). For patients with high-risk MDS assessed using the Cleveland Clinic model formula (n=16/arm), median EFS was 20.2 vs 11.7 months (HR 0.39; 95% CI 0.17–0.90; p=.023); median OS was 24.2 vs 14.2 months (HR 0.45; 95% CI 0.19–1.05; p=.056) with pevonedistat+azacitidine vs azacitidine. Overall response rate (complete remission [CR]+partial remission [PR]+hematological improvement, n=59 response-evaluable patients) was 79% with pevonedistat+azacitidine vs 57% with azacitidine, with a CR rate of 52% vs 27% (p=.050); median duration of response (DOR, CR+PR) was 34.6 vs 13.1 months (p=.106). Median (range) time to transformation (pevonedistat+azacitidine [n=5] vs azacitidine [n=9]) was 12.2 (4.6–12.6) vs 5.9 (1.7–14.8) months. Median dose intensity of azacitidine was 98% in both arms. Exposure-adjusted adverse event (AE) rates, normalized by mean cycles dosed, were lower with pevonedistat+azacitidine vs azacitidine. Pevonedistat+azacitidine clinical activity was observed in patients with adverse-risk mutations. Conclusions: In patients with higher-risk MDS, pevonedistat+azacitidine prolonged EFS, delayed AML transformation, nearly doubled CR rate, and tripled DOR vsazacitidine alone. EFS and OS favored pevonedistat+azacitidine vs azacitidine in patients with high-risk MDS. Exposure-adjusted AE rates were lower with pevonedistat+azacitidine vs azacitidine without added myelosuppression.