Rapid Readouts: Phase 2 Trial of Pevonedistat Plus Azacitidine Versus Azacitidine in Higher-Risk MDS/CMML or LB AML

April 28, 2021
Joshua F. Zeidner, MD, University of North Carolina, Lineberger Comprehensive Cancer Center

Joshua F. Zeidner, MD, presents data from the 62nd American Society of Hematology (ASH) Annual Meeting on an exploratory analysis of patient-reported outcomes from a randomized phase 2 trial of pevonedistat plus azacitidine vs azacitidine in higher-risk myelodysplastic syndrome (MDS)/chronic myelomonocytic leukemia (CMML) or low-blast acute myeloid leukemia (AML).

Joshua F. Zeidner, MD, discusses data from the following presentation:

  • Randomized Phase 2 Trial of Pevonedistat Plus Azacitidine Versus Azacitidine in Higher-Risk Myelodysplastic Syndromes/Chronic Myelomonocytic Leukemia or Low-Blast Acute Myeloid Leukemia: Exploratory Analysis of Patient-Reported Outcomes
    • The objectives of this exploratory analysis are to assess the impact of the addition of pevonedistat to azacitidine on patient-reported outcomes (PROs) and to evaluate the treatment impact on PROs by characterizing their relationship with clinical response and transformation to AML.
    • The phase 2, randomized, open-label, global, multicenter study included patients with higher-risk MDS (n=67), higher-risk CMML (n=17), and low-blast AML (n=36).
    • Patients were randomized 1:1 to receive pevonedistat (20 mg/m2 IV on days 1, 3, 5) plus azacitidine (75 mg/m2 [IV or subcutaneous (SC)] on days 1-5, 8, 9) or azacitidine (75 mg/m2 [IV or SC] on days 1-5, 8, 9).
    • Results in the intent-to-treat (ITT) population1:
      • Median event-free survival (EFS): 21.0 vs 16.6 months (HR, 0.67; 95% CI, 0.42-1.05; P=.076)
      • Median overall survival (OS): 21.8 vs 19.0 months
        (HR, 0.80; 95% CI, 0.51-1.26; P=.334)
      • Overall response rate (ORR; [CR + CRi + PR + HI]): 71% (n=39/55) vs 60% (n=32/53)
    • Post-hoc analyses presented here are in the PRO population (n=112).
      • PRO population all patients with PRO assessment at baseline and greater than or equal to postbaseline PRO assessment in ITT population
      • PROs included as exploratory end points in P-2001 study (NCT02610777)
      • European Organisation for Research and Treatment of Cancer quality of life questionnaire—core 30 items (EORTC QLQ-C30) administered at the first day of each cycle, at the end of treatment (EOT) visit, and post-EOT visits
        • KEY PRO scores of interest: physical functioning, global health status/quality of life, fatigue, and dyspnea
      • Exploratory post-hoc PRO analyses:
        • Rate of available PROs and rate of PROs completion over time as recommended by the Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints (SISAQOL) group2
        • Assessment of change in key PROs over time and compared between arms using repeated measurement mixed models
        • Description of key PROs after clinical response depending on the type of response (CR, PR, CRi, or HI)
        • Description of key PROs before and after HI in patients with higher-risk MDS/CMML who progressed to AML
      • Results
        • No significant difference in the change over time in key PROs between pevonedistat combination and azacitidine
          • No statistically significant change in score over the study
          • No impact of missing data due to progression or death on results (sensitivity analysis)
          • Median number of cycles was 10
        • Improvement (nonsignificant) in physical functioning and fatigue was observed after patients experienced CR as best overall response (n=27) compared with baseline
          • Improvement defined as any positive change for physical functioning and quality of life scores, and any negative change for fatigue and dyspnea scores
          • Similar trend in overall health and dyspnea as well as PR response
          • No trend of improvement in HI in key PROs
        • After transformation to AML, higher-risk MDS/CMML patients reported poorer physician functioning and more severe fatigue
      • Conclusions
        • Findings suggest that the addition of pevonedistat to azacitidine has a similar AE profile to azacitidine alone and does not lead to decrement in the key PROs.
        • Achievement of CR was associated with nonsignificant improvement in PROs compared with baseline independently of the treatment received.
          • In P-2001, CR rates were higher with pevonedistat plus azacitidine vs azacitidine alone.
        • Transformation was associated with the worsening of PROs.
          • Thus, delaying transformation to AML should be a goal of therapy for patients with higher-risk MDS/CMML and may be considered a patient-relevant end point to assess quality of life.
        • PROs analyses were exploratory end points and should be cautiously interpreted.
        • Additional analyses are planned with the P-2001 PRO data


1. Ades L et al. ASCO 2020 annual meeting. Abstract 7506.

2. Coens C et al. Lancet Oncol. 2020;21(2):e83-e96.