EFS Benefit Absent With Frontline Pevonedistat/Azacitidine in Higher-Risk MDS/CMML and Low-Blast AML

The phase 3 PANTHER study of pevonedistat plus azacitidine for the treatment of 3 hematologic malignancies has missed its primary end point.

Pevonedistat (MLN4924) in combination with azacitidine did not achieve a statically significant improvement in event-free survival (EFS) as frontline treatment of patients with higher-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and low-blast acute myeloid leukemia (AML) compared with azacitidine monotherapy, missing the primary end point of the phase 3 PANTHER clinical trial.1

According to a press release issued by Takeda Pharmaceutical Company Limited, an event in the study was defined as death or transformation to AML in participants with higher-risk MDS or CMML, whichever occurs first, or death in participants with AML. The agent also showed a safety profile that was consistent with prior reports.

“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, in a press release. “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 selective NEDD8 inhibitor that has been shown to cause the death of cancer cells through disruption of protein homeostasis.1 In the phase 3, randomized, controlled, open-label PANTHER study, patients received pevonedistat 20 mg/m2, via intravenous infusion over 60 minutes on days 1, 3, and 5 of a 28-day treatment cycle in combination with azacitidine 75 mg/m2 by IV or subcutaneous injection on day 1 to 5, and day 8 and 9 of a 28-day cycle. In the experimental arm or azacitidine alone in the control arm. Both therapies were continued until disease progression or unacceptable toxicity.2

The key secondary end points of the study were overall survival; 6-month, 1-year, 30-day, and 60-day survival rates; time to AML transformation in the higher-risk MDS and CMML groups; and complete response rate.

Approximately 454 patients were enrolled in the study. Those enrolled in the study had morphologically confirmed disease, and ECOG performance status of 0-2, and were required to meet certain TRM score requirements. Those with MDS or CMML were required to high-risk disease based on the Revised International Prognostic Scoring System.

Of the 256 locations testing the efficacy and safety of pevonedistat in these patient populations, 15 locations in the United State have completed their analyses. At the remaining locations, the study is active but no longer recruiting patients.

Full results from the PANTHER study have been submitted to be presented at an upcoming medical congress. All investigators at the 256 locations have been informed of the study results so they can make a decision on the next steps for their patients.1


1. Takeda provides update on phase 3 PANTHER (Pevonedistat-3001) trial. News release. September 2, 2021. Accessed September 2, 2021. https://bit.ly/2WOb76E

2. Participants With higher-risk myelodysplastic syndromes (HR MDS) chronic myelomonocytic leukemia (CMML), or low-blast acute myelogenous leukemia (AML) (PANTHER). Clinicaltrials.gov. Accessed September 2, 2021. https://clinicaltrials.gov/ct2/show/NCT03268954