Pevonedistat plus azacitidine may increase survival for myelodysplastic syndrome, AML
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Pevonedistat plus azacitidine increased overall survival, event-free survival and response rates compared with azacytidine alone in higher-risk myelodysplastic syndromes and low-blast acute myeloid leukemia, according to data presented at ASCO.
Further, pevonedistat (MLN-4924, Millennium/Takeda) plus azacitidine (Vidaza, Celgene) had a comparable safety profile to azacitidine alone in patients with higher-risk myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML), or low-blast AML.
“Pevonedistat is a NEDD8-activating enzyme inhibitor that works on the cellular machinery to stop the growth of cancer cells – in this case, either myelodysplastic cells or acute myeloid leukemia cells,” Mikkael A. Sekeres, MD, MS, physician in the department of hematology and medical oncology at Cleveland Clinic, told Healio.
Investigators randomly assigned 120 patients 1:1 to receive pevonedistat 20 mg/m2 intravenously on days 1, 3 and 5 in combination with azacitidine 75 mg/m2 (IV/subcutaneously) on days 1–5, 8 and 9 (n = 58), or azacitidine monotherapy (n = 62), in 28-day cycles until unacceptable toxicity, relapse, transformation to AML or death, according to the abstract. Primary endpoint was event-free survival.
Sixty-seven patients had higher-risk MDS, another 36 had low-blast AML and 17 had CMML.
Sekeres and colleagues reported an improvement in event-free survival for patients who received the combination, with median event-free survival of 21 months vs. 16.6 months for those who received azacitidine alone (HR = 0.65; 95% CI, 0.41–1.02). They also observed a benefit in patients with higher-risk MDS for the combination, with immediate event-free survival of 20 months vs. 15 months for those who received azacitidine alone (HR = 0.54; 95% CI, 0.29–1).
Although the study was not powered to show a difference in overall survival, OS was also improved, according to Sekeres. In higher-risk MDS patients, median OS was 23.9 months for those who received the combination and 19.1 months for those who received azacitidine monotherapy (HR = 0.7; 95% CI, 0.39–1.27). In low-blast AML patients, the median OS was 23.6 months for those who received the combination and 16 months for those who received monotherapy (HR 0.49; 95% CI, 0.22–1.11).
The researchers also reported the overall response rate was 71% with pevonedistat plus azacitidine compared with 60% with azacitidine monotherapy. In higher-risk MDS, the complete remission rate was 52% vs. 27% (P = .05) with combination therapy vs. monotherapy.
Both common adverse events and serious adverse events occurred at similar rates in patients who received azacitidine monotherapy vs. those who received the combination.
“It seems like the combination was pretty well tolerated and patients were able to stay on it for long enough to see a benefit,” Sekeres said.
Rates of grade 3 or greater adverse events were 90% in those who received the combination and 87% in those who received monotherapy, according to the abstract. The most common events included neutropenia (31% vs. 27%), febrile neutropenia (26% vs. 29%), anemia (19% vs. 27%) and thrombocytopenia (19% vs. 23%). Nine percent of combination patients and 16% of monotherapy patients died during the study.
These findings represent the basis for a current phase 3, randomized study examining the combination vs. azacitidine monotherapy for patients that have higher-risk MDS, Sekeres said.
“The take-home message is that there does seem to be benefit to the combination therapy over azacitidine monotherapy in improving event-free survival with a signal for improving overall survival,” he told Healio.
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Ades L, et al. Abstract 7506. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
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