A randomized phase two study observed no differences in response rates or event-free survival (EFS) with the addition of pevonedistat to the standard-of-care azacitidine plus venetoclax backbone to treat patients with newly diagnosed acute myeloid leukemia (AML), although it did find potential benefit to adding pevonedistat in the IDH-mutated AML subtype.
The results were published in Leukemia & Lymphoma with Nicholas Short, MD, of the University of Texas MD Anderson Cancer Center, listed as the first author.
The study was stopped early following negative results from the phase 3 PANTHER study, which found no statistically significant improvement in EFS with pevonedistat plus azacitidine versus azacitidine alone in patients with higher-risk myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia or low-blast AML. Patient outcomes were analyzed up to the datacut after the study was halted.
For pevonedistat plus azacitidine plus venetoclax (n=83) versus azacitidine plus venetoclax (n=81), the median follow-up was 8.44 versus 7.95 months; the complete remission (CR) rate was 45% versus 49%; composite CR (CCR; CR plus CR with incomplete blood count recovery) was 77% versus 72%. There were no differences in event-free survival (primary endpoint; hazard ratio [HR]: 0.99; 95% confidence interval [CI]: 0.61–1.60; P=0.477) or overall survival (HR, 1.42; 95% CI, 0.82–2.49; P= 0.896).
However, in exploratory analyses in IDH-mutated AML, the CCR rate for the pevonedistat plus azacitidine plus venetoclax arm was 95% (20/21), versus 62% (13/21) in the azacitidine plus venetoclax arm (P=0.013 adjusted for age and AML subtype based on prespecified randomization stratification factors).
Safety was similar between treatment arms. Efficacy/safety with azacitidine plus venetoclax was consistent with the earlier phase 3 VIALE-A study.
“Although the addition of pevonedistat to azacitidine plus venetoclax failed to significantly improve response rates or EFS in patients with newly diagnosed AML who were unfit for intensive chemotherapy, this randomized study confirms the efficacy and safety of the azacitidine plus venetoclax standard-of-care first described in VIALE-A, with potential benefit of adding pevonedistat in IDH-mutated AML,” the authors concluded.
Reference
Short NJ, Wierzbowska A, Cluzeau T, et al. Azacitidine and venetoclax with or without pevonedistat in patients with newly diagnosed acute myeloid leukemia. Leuk Lymphoma. 2025;66(3):458-468. doi:10.1080/10428194.2024.2431878
