It’s a trial, a phase II trial, that is dedicated to patients with high risk MDS, high risk CMML and patients with low blast count AML. In this population, especially patients with high risk MDS, the treatment of choice nowadays is hypomethylating agent, especially azacitidine. This drug is the cornerstone of the treatment of high risk MDS. So far we have seen many trials attempting to improve the results of azacitidine but, for the moment, all those trials, at least in high risk MDS, failed to show any advantage over azacitidine alone.
What was the design of the trial?
This is a phase II study for patients with high risk MDS, high risk CMML or low blast EML who had not been previously treated with hypomethylating agents and were ineligible for stem cell transplantation. These patients were randomised one to one to receive pevonedistat plus azacitidine or azacitidine alone. The study was powered on event free survival as the original primary endpoint.
What were the results?
Overall 120 patients have been enrolled. The median age in the study was 70 years. 56% of the patients had high risk MDS, 14% had high risk CMML and 30% had low blast AML. In terms of the results, regarding the results, in the intention to treat population there was a trend towards longer event free survival with pevonedistat plus azacitidine versus azacitidine alone. The median EFS was 21 months for the combination, versus 16.6 months for azacitidine alone. The median overall survival was 21.8 months with pevonedistat and azacitidine compared to 19 months with azacitidine alone. Even if the study was not powered to observe differences in disease specific subgroups, in patients with high risk MDS median event free survival was significantly longer with the combination of pevonedistat and azacitidine versus azacitidine alone with a median event free survival of more than 20 months compared to 14.8 months with azacitidine alone.
Similarly, in patients with low blast AML the overall survival with pevonedistat and azacitidine versus azacitidine alone trended towards significance with a median overall survival of 23.6 months versus 16 months.
Overall response was a secondary endpoint and among patients with high risk MDS the overall response rate was higher with the combination of pevonedistat and azacitidine compared to azacitidine alone. The median duration of response in these patients was 34.6 months with pevonedistat and azacitidine versus 13.1 months with azacitidine alone. So these are the key results of the study.
Were there any toxicities/adverse events?
In terms of toxicity, the toxicity profile observed within the study was similar across the two groups. There was no myelosuppression that was added by the addition of pevonedistat to azacitidine. So the toxicity profile was similar in the two groups.
What were the main conclusions?
The main conclusion is that it’s a promising result. This is a promising result because in the intention to treat analysis pevonedistat plus azacitidine led to a trend towards improved event free survival. There were also encouraging clinical efficacy results with the combination of pevonedistat and azacitidine in high risk MDS and low blast AML.
A randomised phase III trial is fully enrolled and is further evaluating the combination of pevonedistat and azacitidine versus azacitidine alone in the same population. We look forward for the results of this study. If it confirms, and maybe even amplifies, the promising results of this phase II we will have a new treatment for high risk MDS. But for the moment we have to be careful and wait for the final result of the phase III study.