Takeda Pharmaceutical Company Limited announced the results of the Phase 2 Pevonedistat-2001 trial. The study evaluated a cyclodextrin-enabled (SBECD) pevonedistat plus azacitidine versus azacitidine alone in patients with rare leukemias, including higher-risk myelodysplastic syndromes (HR-MDS). These results show that the combination of pevonedistat and azacitidine is a highly active, promising therapeutic approach and suggest benefit in the HR-MDS subgroup across multiple clinically meaningful endpoints, including overall survival (OS), event-free survival (EFS), complete remission (CR) and transfusion independence, with a safety profile similar to azacitidine alone.
There have been no treatment advancements for HR-MDS in more than a decade and current treatment options provide limited benefit. Pevonedistat could be the first new treatment option for these patients.
Key findings, to be presented by Dr. Lionel Adès, include:
- Intent to treat population (n=120):
- Median OS was 21.8 months (mos.) in the pevonedistat combination arm, vs. 19.0 mos. with azacitidine alone (HR 0.802; p = 0.334).
- EFS trended longer in the pevonedistat combination arm vs. azacitidine alone with a median of 21.0 mos. vs. 16.6 mos.
- HR-MDS Subgroup (n=67):
- Median OS in the pevonedistat combination arm alone was 23.9 mos. vs. 19.1 mos. with azacitidine alone.
- Median EFS in the pevonedistat combination arm was 20.2 mos. vs. 14.8 mos. with azacitidine alone.
- Overall response rate (ORR) in the pevonedistat combination arm was 79.3% vs. 56.7% with azacitidine alone.
- CR rate in the pevonedistat combination arm was 51.7% vs. 26.7% with azacitidine alone.
- Median duration of response (DoR) in the pevonedistat combination arm was 34.6 months vs. 13.1 mos. with azacitidine alone.
- Of the patients who were red blood cell (RBC) transfusion dependent at baseline, 69.2% receiving pevonedistat plus azacitidine vs. 50.0% receiving azacitidine alone became transfusion independent.
- LB-AML (n=36) & HR-CMML (n=17) Subgroups:
- Median OS in LB-AML was 23.6 mos. in the pevonedistat combination arm vs. 16.0 mos. with azacitidine alone.
- Median OS and EFS in HR-CMML favored the azacitidine alone arm, which may be due to low sample size and/or greater patient heterogeneity.
- Safety data includes:
- The safety profile of pevonedistat combined with azacitidine was similar to azacitidine alone, and did not lead to increased myelosuppression.
- The most common grade ≥3 AEs across both arms were neutropenia (33% vs. 27%), febrile neutropenia (26% vs. 29%), decreased neutrophil count (21% vs. 10%), anemia (19% vs. 27%), thrombocytopenia (19% vs. 23%), and pneumonia (12% vs. 10%).
- On-study deaths occurred in 9% of patients in the pevonedistat combination arm versus 16% with azacitidine alone.
Pevonedistat is a first in class NEDD8-activating enzyme (NAE) inhibitor, which blocks modifications of select proteins. Pevonedistat treatment disrupts cell cycle progression and cell survival, leading to cell death in cancers including leukemias. Pevonedistat in combination with azacitidine demonstrated antitumor activity in preclinical studies and was well tolerated, with promising clinical activity, in a Phase 1 study of patients with AML. Pevonedistat is currently being evaluated in Phase 3 studies as a first-line treatment for patients with HR-MDS, HR-CMML, and AML, who are ineligible (unfit) for transplant or intensive induction chemotherapy and is also being explored in a Phase 2 study in unfit AML in a triple combination with azacitidine and venetoclax.