Joshua Zeidner, MD from the University of North Carolina, Lineberger Comprehensive Cancer Center discusses the ASH 2020 abstract – 2191 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.
Introducing
P-2001, a randomized phase 2 trial (NCT02610777), examined the efficacy and safety of pevonedistat (P), the first small molecule NEDD8-activating enzyme inhibitor, in combination with azacitidine (A) versus A alone in higher-risk patients (pts) with myelodyspla (Revised International Prognostic Scoring System risk >3, including intermediate [approximately 5% blasts], high or very high risk) The P-2001 study recently reported a median event-free survival of 21.0 months vs 16.6 months (HR=0.665; P=.076) and a 71 percent (n=39/55) overall response rate (complete remission [CR] + CR with incomplete blood count recovery [CRi] + partial response [PR] + hematological improvement [HI]) vs 60 percent (n=32/53) with P+A vs. A. MDS management may have a huge effect on the quality of life and high symptom burden measurements have been correlated with worse health results. As an exploratory outcome in the research, we set out to investigate patient-reported findings (PRO).
Methodology
The research randomized 120 pts (1:1) into 28-day treatment periods to receive P+A or A alone. On the first day of each cycle, at the conclusion of treatment (EOT) and post-EOT visits, the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 Items (QLQ-C30) was administered. The key PRO concepts that required special attention in this population were defined as physical functioning (PF), exhaustion (FA), dyspnea (DY), and global health status/quality of life (QL). Analyses were performed to explore PRO data: an overview of available PRO data, longitudinal analysis of changes in key PRO repeat measurement mixed models (RMMM) scores, including a comparison between treatment arms, and descriptive analysis of key PRO scores after clinical response by type of response (PR, CR, CRi, or HI) and before and after the transition to AMMS.
Outcomes
In the PRO population, there were 112 pts (defined as all pts with a baseline and at least 1 post-baseline PRO assessment); baseline demographics and disease characteristics are presented in Table 1. In each period at least 90% of the pts in the study had a PRO available. As predicted due to progression, death, or discontinuation of the study, the amount of available PRO data decreased during the study. The PRO population’s RMMMs did not show any statistically significant difference between P+A versus A alone in the shift over time in main QLQ-C30 scores (PF, QL, FA, and DY). There was a non-significant increase in PF and QL, as well as a non-significant decrease in FA after CR than at baseline in Pts who witnessed CR (P+A, 40 percent; A, 29 percent); no discrepancies were noticed in DY. In the main PROs, Pts for which PR was the best response had less improvement than pts with CR, and those with HI showed no improvement compared to baseline. Among the 12 pts with higher-risk MDS/CMML progressing to AML during the analysis with available PRO data (P+A, n=4; A, n=8), 6 showed PF score worsening (vs 2 improving), 6 showed QL score worsening (vs 1 improving), 7 showed FA score worsening (vs 1 improving), and 7 showed DY score worsening (vs 1 improving) (vs none improving).
Findings
In the assessment of new therapies in higher-risk MDS/CMML and LB AML, QL calculation and symptom burden are integral clinical endpoints. There was no evidence to indicate that the addition of P to A contributed to an improvement in the established primary PROs: QL, PF, FA, and DY. Compared to baseline, the achievement of CR was associated with higher PRO scores regardless of the care obtained, and progression to AML was associated with deteriorating QL scores. In order to further explore the influence of P on PROs by assessing the impact of dropout during the analysis, comparing outcomes by treatment arm, and better understanding the potential effect of adverse effects on PROs, additional studies are planned with the P-2001 PRO data.