Pevonedistat Plus Azacitidine Shows Clinical Efficacy in Higher-Risk MDS and Low-Blast AML

Results from a randomized, proof-of-concept, phase II study demonstrated promising overall survival (OS), event-free survival (EFS), and overall response rates (ORR) in patients with higher-risk myelodysplastic syndromes (HR-MDS) and low-blast acute myeloid leukemia (LB-AML). These findings were published in Leukemia.

“Pevonedistat is the first small-molecule inhibitor of the neural precursor cell expressed, developmentally downregulated 8 (NEDD8)-activating enzyme (NAE),” the authors explained. “Inhibition of NAE by pevonedistat prevents degradation of CRL substrates integral to tumor cell growth, proliferation, and survival, thereby leading to cancer cell death.”

This study enrolled 120 patients with morphologically confirmed higher-risk MDS, non-proliferative chronic myelomonocytic leukemia (CMML), or LB-AML. The participants were randomized 1:1 to receive 28-day cycles of either pevonedistat 20 mg/m2 on days 1, 3, and 5, plus azacitidine 75 mg/m2 on days 1-5 and 8-9 (n = 58) or azacitidine alone on the same schedule (n=62).

After a median follow-up of 21.4 in the pevonedistat + azacitidine arm and 19.0 months in the azacitidine arm, the combination demonstrated clinically meaningful increases compared with azacitidine alone (median OS = 21.8 months vs. 19.0 months; median EFS = 21.0 vs. 16.6 months). Among 108 response-evaluable patients, the ORR with pevonedistat + azacitidine versus azacitidine was 70.9% versus 60.4%, and the median duration of response was 20.6 months versus 13.1 months.

Overall, the safety profile of pevonedistat + azacitidine was comparable to that of azacitidine alone, the authors noted. The most common grade ≥3 treatment-emergent adverse events (TEAEs) were neutropenia (33% vs. 27%), febrile neutropenia (26% vs. 29%), anemia (19% vs. 27%), and thrombocytopenia (19% vs. 23%).

“Given the encouraging clinical activity in combination with azacitidine, its novel mechanism of action, and its nonmyelosuppressive safety profile, pevonedistat may be an ideal combination partner with other agents, such as venetoclax, as the treatment landscape evolves,” the authors concluded.