Pevonedistat Added to Azacitidine Promising for Higher-Risk MDS

Pevonedistat plus azacitidine yields comparable safety to azacitidine monotherapy and demonstrates improved overall survival (OS), event-free survival (EFS), and response rates in patients with higher-risk myelodysplastic syndromes (MDS), according to results from a phase 2 study.

“[Pevonedistat], 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…[azacitidine] in AML,” wrote Lionel Ades, MD, Hôpital Saint-Louis, Paris, France, and colleagues.

This phase 2 study evaluated pevonedistat in combination with azacitidine in patients with higher-risk MDS, chronic myelomonocytic leukemia (CMML), or low-blast acute myelogenous leukemia (LB-AML). A total of 120 patients naïve to hypomethylating agents were enrolled on the trial and randomized in a 1:1 ratio to pevonedistat plus azacitidine (n = 58) or azacitidine alone (n = 62).

Pevonedistat was administered intravenously (IV) at 20mg/m² on days 1, 3, and 5, and azacitidine was administered IV/subcutaneously at 75mg/m² on days 1-5, 8, and 9 of 28-day cycles until unacceptable toxicity, relapse, transformation to AML or progression.

The primary end point of the trial was OS, although Dr Ades and colleagues noted that the trial was underpowered for OS.

Patients in the combination arm received a median of 13 cycles of therapy compared with 8.5 cycles in the azacitidine monotherapy arm. Median OS was 21.8 months versus 19 months, respectively (hazard ratio [HR] 0.80; 95% CI 0.51–1.26; P = .334; median follow-up 21.4 vs 19 months).

Additionally, subanalyses for disease type showed median OS with combination therapy of 23.9 months in higher-risk MDS (n = 67) compared to 19.1 months with azacitidine monotherapy (HR 0.70; 95% CI 0.39–1.27; P = .240), and 23.6 months versus 16 months, respectively in LB-AML (n = 36; HR 0.49; 95% CI 0.22–1.11; P = .081).

Median EFS was 21 months with combination therapy compared with 16 months with azacitidine monotherapy (HR 0.65; 95% CI 0.41–1.02; P = .060) and was significantly longer in patients with higher risk MDS (20.2 vs 14.8 months; HR 0.54; 95% CI 0.29–1.00; P = .045).

In response-evaluable patients, overall response rate was 71% (39 of 55 patients) with combination therapy compared with 60% (32 of 53 patients with azacitidine alone. In patients with higher-risk MDS, the complete response rate was 52% versus 27% (P = .050), respectively.

Grade ≥3 adverse events (AEs) were reported for 90% of patients on combination therapy versus 87% of patients receiving azacitidine alone. The most common AEs were neutropenia (31% vs 27%, respectively), febrile neutropenia (26% vs 29%), anemia (19% vs 27%) and thrombocytopenia (19% vs 23%). On-study deaths occurred in 9% of patients who received combination therapy and 16% of patients who received azacitidine alone.

“[Pevonedistat plus azacitidine] had a comparable safety profile to…[azacitidine] alone, did not increase myelosuppression, and maintained… [azacitidine] dose intensity,” Dr Ades and colleagues concluded.

“Although not statistically significant, P+A increased OS, EFS, and response rates vs A, particularly in pts with higher-risk MDS,” they added, noting that further evaluation is ongoing in a randomized trial.—Janelle Bradley

Ades L, Watts JM, Radinoff A, et al. 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). Presented at: the 2020 ASCO Annual Meeting; May 29-31, 2020. Abstract 7506.