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

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.