Pevonedistat/Azacitidine Misses EFS End Point in Frontline Higher-Risk MDS/CMML, Low-Blast AML

The combination of pevonedistat plus azacitidine as a frontline treatment for patients with higher-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and low-blast acute myeloid leukemia (AML) did not achieve predefined statistical significance for the primary end point of event-free survival (EFS) in the phase 3 PANTHER (Pevonedistat-3001; NCT03268954) trial, according to Takeda Pharmaceutical Company Limited.¹

Full findings from the PANTHER study, which are currently being evaluated, will be presented at an upcoming medical meeting. The safety data were found to be consistent with previously reported findings of the combination of pevonedistat and azacitidine.

“While we are disappointed with this outcome, we are continuing to gain a greater understanding of the full data set and hope that findings from this Phase 3 study will provide information to help guide research and development for potential treatment options for these underserved patient populations,” said Chris Arendt, PhD, head, Oncology Cell Therapy and Therapeutic Area Unit, Takeda, the developer of pevonedistat. “We would like to thank the patients, families, advocacy organizations and investigators that participated in this trial, without whom this meaningful research would not have been possible. Takeda remains committed to conducting important research and transforming the lives of patients with cancer.”

Pevonedistat is a NEED8-activating enzyme that leads to cancer cell death by disrupting protein homeostasis. In July 2020, the FDA had granted a breakthrough therapy designation to pevonedistat for the treatment of patients with higher-risk MDS.

Previously reported results of the phase 2 trial Pevonedistat-2001 trial (NCT02610777), which also evaluated pevonedistat in combination with azacitidine vs azacitidine alone in patients with higher-risk MDS, low-blast AML, and CMML, showed that in the subgroup of patients with higher-risk MDS, the median EFS was 20.2 months with the combination vs 14.8 months with azacitidine alone (HR, 0.539; 95% CI, 0.292-0.995; P = .045).²

Additionally, the median overall survival (OS) in the investigative arm was 23.9 months vs 19.1 months in the control arm. The objective response rates were 79.3% vs 56.7%, respectively, in those with higher-risk MDS.

In the randomized, controlled, open-label, phase 3 PANTHER trial, approximately 454 patients with higher-risk MDS, CMML, or low-blast AML were treated with pevonedistat/azacitidine or azacitidine alone. Pevonedistat was given at 20 mg/m² and azacitidine intravenously at 75 mg/m².

This multicenter study was conducted Spain, Belgium, Brazil, Canada, Czech Republic, France, Germany, Israel, Italy, United States, Australia, Greece, Japan, Mexico, Poland, Russia, Korea, Turkey, China, and United Kingdom.

Regarding the primary end point, an event was defined as death or transformation to AML in patients with higher-risk MDS or CMML, whichever occurs first, and death in patients with AML. Secondary end points were OS; 30-day, 60-day, 6-month, and 1-year OS rates; time to AML transformation; overall response and complete remission rates; duration of response; health-related quality of life.

Further analyses presented at the 2021 European Hematology Association Congress showed that pevonedistat demonstrated a favorable risk-benefit profile at a 20 mg/m² dose when given in combination with azacitidine at 75 mg/m² in patients with higher-risk MDS/CMML and AML. The results were of a model-based analysis based on data from 3 trials.⁴

References

1. Takeda Provides Update on Phase 3 PANTHER (Pevonedistat-3001) Trial. News release. Takeda Pharmaceutical Company Limited. September 1, 2021. Accessed September 2, 2021. https://bit.ly/3gVwAS1
2. Sekeres MA, Watts J, Radinoff A, et al. Randomized phase 2 trial of pevonedistat plus azacitidine versus azacitidine for higher-risk MDS/CMML or low-blast AML. Leukemia. 2021;35(7):2119-2124. doi:10.1038/s41375-021-01125-4
3. Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine as First-Line Treatment for Participants With Higher-Risk Myelodysplastic Syndromes (HR MDS), Chronic Myelomonocytic Leukemia (CMML), or Low-Blast Acute Myelogenous Leukemia (AML) (PANTHER). ClinicalTrials.gov. Updated August 11, 2021. Accessed September 2, 2021. https://clinicaltrials.gov/ct2/show/NCT03268954
4. Zhou X, Mould D, Zhao D, et al. Dose selection of pevonedistat + azacitidine in patients with higher-risk myelodysplastic syndromes/chronic myelomonocytic leukemia and acute myeloid leukemia: a model-based analysis. Presented at: 2021 European Hematology Association Congress; June 9-17, 2021; virtual. Abstract EP928.