Pevonedistat plus azacitidine prolongs EFS in higher-risk myelodysplastic syndrome
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The addition of pevonedistat to azacitidine prolonged EFS among patients with higher-risk myelodysplastic syndrome, according to results of a phase 2 study presented at Society of Hematologic Oncology Annual Meeting.
The safety profile of the combination appeared comparable to that of azacitidine (Vidaza, Celgene) alone, researchers noted.
Pevonedistat (TAK-924, Takeda), a small-molecule inhibitor of NEDD8-activating enzyme, works by disrupting proteasomal degradation of select proteins.
Justin M. Watts, MD, hematologist/oncologist at Sylvester Comprehensive Cancer Center and assistant professor at University of Miami, and colleagues evaluated data from patients with higher-risk myelodysplastic syndrome/chronic myelomonocytic leukemia — defined as those with a Revised International Prognostic Scoring System score of 3 or higher — or low-blast count acute myeloid leukemia naive to treatment with hypomethylating agents.
Researchers randomly assigned 58 patients to 20 mg/m2 IV pevonedistat at on days 1, 3, and 5 in combination with 75 mg/m2 IV azacitidine on days 1 through 5, 8 and 9 of each 28-day cycle. The other 62 patients received azacitidine alone.
EFS served as the primary endpoint.
OS, overall response rate and safety served as secondary endpoints. Researchers evaluated patient-reported quality of life using the European Organization for Research and Treatment of Cancer Questionnaire-C30.
In the intent-to-treat population of 120 patients, researchers reported a trend toward improved EFS (21 months vs. 16.6 months; HR = 0.67; 95% CI , 0.42-1.05) and OS (21.8 months vs. 19 months; HR = 0.8; 95% CI, 0.51-1.26) among patients who received the combination compared with those who received azacitidine alone, although the improvements did not reach statistical significance.
Among 67 patients with higher-risk myelodysplastic syndrome, researchers observed improved EFS (median, 20.2 months vs. 14.8 months; HR = 0.54; 95% CI, 0.29-1) and a trend toward improved OS (median, 23.9 months vs. 19.1 months; HR = 0.7; 95% CI, 0.39-1.27) among those who received pevonedistat plus azacitidine.
Among 59 response-evaluable patients with higher-risk MDS, ORR was 79% with the combination vs. 57% with azacitidine alone. Researchers reported a median duration of response of 34.6 months in the combination therapy group and 13.1 months in the monotherapy group.
Median azacitidine dose intensity remained at 98% among patients with higher-risk MDS in both treatment groups.
Ninety-four percent of patients who received combination therapy, as well as 83% of patients who received monotherapy, experienced grade 3 or higher adverse events. The most common of these included neutropenia (combination, 38% vs. monotherapy, 37%) and febrile neutropenia (22% vs. 31%).
Researchers observed no difference in patient-reported quality of life between both groups.
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Watts J, et al. Abstract MDS-336. Presented at: Society of Hematologic Oncology Annual Meeting (virtual meeting). Sept. 9-12, 2020.
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