Pevonedistat plus azacitidine vs azacitidine alone in higher-risk MDS/chronic myelomonocytic leukemia or low-blast-percentage AML

Abstract

PANTHER is a global, randomized phase 3 trial of pevonedistat+azacitidine (n = 227) vs azacitidine monotherapy (n = 227) in patients with newly diagnosed higher-risk myelodysplastic syndromes (MDS; n = 324), higher-risk chronic myelomonocytic leukemia (n = 27), or acute myeloid leukemia (AML) with 20% to 30% blasts (n = 103). The primary end point was event-free survival (EFS). In the intent-to-treat population, the median EFS was 17.7 months with pevonedistat+azacitidine vs 15.7 months with azacitidine (hazard ratio [HR], 0.968; 95% confidence interval [CI], 0.757-1.238; P = .557) and in the higher-risk MDS cohort, median EFS was 19.2 vs 15.6 months (HR, 0.887; 95% CI, 0.659-1.193; P = .431). Median overall survival (OS) in the higher-risk MDS cohort was 21.6 vs 17.5 months (HR, 0.785; P = .092), and in patients with AML with 20% to 30% blasts was 14.5 vs 14.7 months (HR, 1.107; P = .664). In a post hoc analysis, median OS in the higher-risk MDS cohort for patients receiving >3 cycles was 23.8 vs 20.6 months (P = .021) and for >6 cycles was 27.1 vs 22.5 months (P = .008). No new safety signals were identified, and the azacitidine dose intensity was maintained. Common hematologic grade ≥3 treatment emergent adverse events were anemia (33% vs 34%), neutropenia (31% vs 33%), and thrombocytopenia (30% vs 30%). These results underscore the importance of large, randomized controlled trials in these heterogeneous myeloid diseases and the value of continuing therapy for >3 cycles. The trial was registered on clinicaltrials.gov as #NCT03268954.

Graphical abstract

Figure 1.

Distribution of poor prognostic and frequently mutated genes in patients with higher-risk MDS by treatment arm. Mutational analysis was conducted on 270 bone marrow aspirate samples collected at screening (n = 135 samples from each treatment arm).

Figure 2.

EFS and OS in the ITT population. Kaplan-Meier curve of EFS (A) and Kaplan-Meier curve of OS (B). ITT, intent-to-treat.

Figure 3.

EFS in the higher-risk MDS cohort. Kaplan-Meier curve of EFS (A) and forest plot of subgroup analysis of EFS (B). *Lower confidence interval is truncated at 0.125. NE, not estimable.

Figure 4.

OS in the higher-risk MDS cohort.

Figure 5.

OS in patients with AML with 20% to 30% blasts. Kaplan-Meier curve of OS (A) and forest plot of subgroup analysis of OS (B). *Upper confidence interval is truncated at 8 and lower confidence interval is truncated at 0.125. ELN, European LeukemiaNet; NE, not estimable; WBC, white blood cell.

Figure 6.

EFS and OS in patients with higher-risk CMML. Kaplan-Meier curve of EFS (A) and Kaplan-Meier curve of OS (B). NE, not estimable.

Figure 7.

OS in patients with higher-risk MDS by number of cycles received. Patients who received greater than 3 cycles (A) and patients who received greater than 6 cycles (B).