The investigational drug pevonedistat in combination with azacitidine injection (Vidaza) leads to longer event-free survival (EFS) and a higher complete response rate than azacitidine alone in patients with high-risk myelodysplastic syndromes (MDS), according to results from a phase 2, open-label, international clinical trial. The findings were presented by Mikkael A. Sekeres, MD, MS, Director, Leukemia Program, Cleveland Clinic, OH, at ASH 2020.
Treatment with pevonedistat—a first-in-class inhibitor of the NEDD8-activating enzyme—disrupts cell-cycle progression and cell survival, leading to tumor cell death. It exhibits synergistic activity in combination with azacitidine in cellular and mouse xenograft models of acute myeloid leukemia (AML).
In this study, 120 patients with high-risk MDS, high-risk chronic myelomonocytic leukemia, and low-blast AML were randomized to pevonedistat 20 mg/m2 intravenously on days 1, 3, and 5, plus azacitidine 75 mg/m2 (intravenous or subcutaneous injection) on days 1 to 5, 8, and 9, or to azacitidine injection monotherapy.
In the intent-to-treat population, the median EFS was 21 months in the pevonedistat plus azacitidine arm versus 16.6 months in the azacitidine monotherapy arm, which did not reach significance (hazard ratio [HR], 0.67; P = .076). The median overall survival (OS) was 21.8 months versus 19 months, respectively, a not significant difference (HR, 0.80; P = .334).
The data presented at the ASH meeting focused on the 67 patients enrolled with high-risk MDS, which was defined (1) as a prognostic risk category of very high (>6 points), high (>4.5-6 points), or intermediate (>3-4.5 points, and ≥5% bone marrow myeloblasts) according to the International Prognostic Scoring SystemRevised (IPSS-R), and (2) according to the Cleveland Clinic model, which is a weighted formula that incorporates clinical and genetic factors, including EZH2, SF3B1, and TP53 mutations.
The EFS and OS favored the combination of pevonedistat plus azacitidine over azacitidine alone among patients with high-risk MDS according to IPSS-R. In this subgroup, the median EFS was 20.2 months in the combination arm versus 14.8 months in the azacitidine-alone arm (HR, 0.539; P = .045).
“This difference in EFS was particularly evident in those patients who were in the higher-risk categories of the IPSS-R,” Dr Sekeres said.
The median OS was 23.9 months and 19.1 months in the combination and monotherapy arms, respectively (HR, 0.701; P = .240).
“The trial wasn’t powered to show differences in OS,” Dr Sekeres added.
In patients who had high-risk MDS (based on the Cleveland Clinic model), the EFS and OS were superior in the combination arm versus the azacitidine-alone arm. The median EFS was 20.2 months and 11.7 months in the 2 arms, respectively (HR, 0.388; P = .023), and the median OS was 24.2 months and 14.2 months, respectively (HR, 0.447; P = .056).
The complete response rate was doubled (52% vs 27%) and the median duration of response was almost tripled (34.6 vs 13.1 months) with pevonedistat plus azacitidine. The median time to first complete response or partial response among responders was shorter in the combination arm at 3.83 months versus 4.29 months in the monotherapy arm.
The rate and duration of transfusion independence were increased with the addition of pevonedistat to azacitidine. The rates of red blood cell and platelet transfusion independence were 69.2% in patients randomized to the combination compared with 47.4% of those assigned to azacitidine alone, a not significant difference (P = .228), but the median duration of transfusion independence was 23.3 versus 11.6 months, respectively, a significant difference (HR, 0.11; P = .016).
Among patients with high-risk MDS that transformed to AML (5 patients in the pevonedistat plus azacitidine arm and 9 in the azacitidine-alone arm), the median time to transformation was delayed in those receiving the combination compared with azacitidine alone (12.2 vs 5.9 months, respectively).
The median OS was 2.56 months from the time of transformation to AML. The median OS was 27.7 months in the 53 patients whose disease did not transform to AML versus 13.6 months among the 14 patients whose disease did (HR, 0.289; P = .0002).
“Clinical activity of pevonedistat-azacitidine was observed in patients with higher-risk MDS who had poor-risk cytogenetics and in patients with adverse risk mutations, including TP53,” said Dr Sekeres.
Exposure-adjusted adverse event rates were lower with the pevonedistat plus azacitidine combination, without added myelosuppression. The rates of grade 3 or 4 adverse events normalized to the duration of treatment were 30% in those who received the combination and 29% in those who received monotherapy.