Phase II study of pevonedistat (P) + azacitidine (A) versus A in patients (pts) with higher-risk myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML), or low-blast acute myelogenous leukemia (LB AML) (NCT02610777).

Abstract

7506 Background: P, the first and only small-molecule inhibitor of the NEDD8-activating enzyme, disrupts proteasomal degradation of select proteins and has shown promising clinical activity and good tolerability in combination with A in AML. Methods: 120 pts with higher-risk (Revised International Prognostic Scoring System risk > 3) MDS/CMML or LB AML naïve to hypomethylating agents were randomized 1:1 to receive P 20 mg/m 2 intravenously (IV) on days (d) 1, 3, 5 + A 75 mg/m 2 (IV/subcutaneously) on d 1–5, 8, 9 (n = 58), or A alone (n = 62), in 28-d cycles until unacceptable toxicity, relapse, transformation to AML, or progression. The primary endpoint was overall survival (OS), although the study was underpowered for OS. Results: Baseline characteristics were generally balanced between arms. Pts received a median of 13.0 vs 8.5 cycles of P+A vs A. Median OS in the intent-to-treat (ITT) population with P+A vs A (n = 120) was 21.8 vs 19.0 mos (hazard ratio [HR] 0.80; 95% CI 0.51–1.26; P = .334; median follow-up 21.4 vs 19.0 mos). Subanalyses showed median OS with P+A vs A in higher-risk MDS (n = 67) of 23.9 vs 19.1 mos (HR 0.70; 95% CI 0.39–1.27; P = .240) and in LB AML (n = 36) of 23.6 vs 16.0 mos; HR 0.49; 95% CI 0.22–1.11; P = .081). Event-free survival (EFS – time from randomization to death/transformation to AML) with P+A vs A trended longer in the ITT population (median 21.0 vs 16.6 mos; HR 0.65; 95% CI 0.41–1.02; P = .060) and was significantly longer in higher-risk MDS (median 20.2 vs 14.8 mos; HR 0.54; 95% CI 0.29–1.00; P = .045). In response-evaluable pts, overall response rate was 71% (n = 39/55; 46% complete remission [CR] + CR with incomplete blood count recovery [CRi], 5% partial response [PR], 20% hematologic improvement [HI]) with P+A vs 60% (n = 32/53; 38% CR+CRi, 8% PR, 15% HI) with A. In higher-risk MDS, CR rate was 52% vs 27% ( P = .050) with P+A vs A. Median A dose intensity was 97% vs 98% with P+A vs A. Rates of grade ≥3 adverse events were 90% vs 87% with P+A vs A; the most common were 31% vs 27% neutropenia, 26% vs 29% febrile neutropenia, 19% vs 27% anemia, and 19% vs 23% thrombocytopenia. On-study deaths occurred in 9% of P+A pts and 16% of A pts. Conclusions: P+A had a comparable safety profile to A alone, did not increase myelosuppression, and maintained A dose intensity. Although not statistically significant, P+A increased OS, EFS, and response rates vs A, particularly in pts with higher-risk MDS. Further evaluation of P+A vs A is ongoing in a randomized phase. Clinical trial information: NCT02610777 .