EHA 2025 | A Phase I/II trial of all-oral DEC-C plus venetoclax in AML ineligible for induction chemotherapy

It was my pleasure to have the opportunity to present data at EHA 2025 on the all oral combination of DEC-C which is oral decitabine and cedazuridine. I’m going to call it oral decitabine for simplicity and venetoclax in older patients or those unfit for intensive induction chemotherapy. And what I talked about was basically well known in the field that the combination of a hypomethylating agent, either azacitidine, decitabine, or also low-dose cytarabine, along with venetoclax is the standard of care for patients with AML who are older, or actually for those over 18 who are unfit for intensive induction. And this is really the worldwide standard. But we came to this standard because the parenteral versions of azacitidine and decitabine, which had been widely used as a single agent for AML, just didn’t work very well. So about nine months median survival. And also actually are a pain for patients because there is a lot of tracking back and forth to either the hospital or the infusion center in order to get their therapy. So our goal was actually to use the oral version of decitabine along with venetoclax to first check whether there were any pharmacokinetic interactions between the drugs and then also to have a look at the efficacy. How long was the complete remission and how long was overall survival? So the trial results were presented. I talked about the Phase I, IIa, and IIb studies with the IIb portion being the pivotal portion. And what we were able to show was, first of all, there were no drug-drug interactions. So that primary endpoint was met. And then the second endpoint, which was the response endpoint for the IIb, was also met with very strong CR rate, 46.5%, strong overall survival at 15.5 months. And actually, these rates were really consistent through the study. It’s not totally unpredicted. So we already knew that oral decitabine was running both pharmacokinetically and from an efficacy perspective about the same as the IV version. And actually in the EU, there is already a label for oral decitabine as a single agent for AML. But these data really solidified that from a safety perspective, from a PK perspective, from a tolerability perspective, everything was tracking for this all-oral combination, to look, as we would expect from a safety perspective also, and from an early mortality perspective, about the same as what the standard parenteral decitabine combination is. So we are very much hoping that this can be a potential new standard of care for patients. This, of course, has to go through regulatory approvals. But the goal would be to get patients to be able to spend more time at home. And I think it was discussed actually throughout the meeting, including at some of the other sessions that I was involved with, that it doesn’t mean that you can give patients pills and send them home and say, good luck. So these patients need monitoring. There is absolutely myelosuppression, including in the post-remission setting. But what we tried to show with these data would be that patients who are doing well can in fact spend more time at home because they don’t have to come in for parenteral administration. And also in the post-remission setting, once you have had blast clearance and demonstration of response, the idea is that the dosing days of venetoclax go down. So you’re actually able to show that as you go to cycle two, cycle three, cycle four, you are able to deliver fewer days of venetoclax. On that topic, and this came up in other sessions multiple times was the concept of optimization of this type of regimen for our AML patients because we want to have the efficacy especially for the high benefit patients who really do have prolonged survival but at the same time you want to mitigate myelosuppression in the post-remission setting. So I was asked multiple times throughout the meeting in different sessions well how many days of venetoclax do you need for these patients once they’re in remission. The data are accumulating. It is definitely not the case that you can simply reduce to any number you want and expect the same efficacy, in particular for the high benefit patients, for some of the NPM1 patients, IDH patients who really have very strong benefit with ongoing administration. We do not recommend randomly dose adjusting to low numbers of days of venetoclax in the post-remission setting, but we are trying to accumulate data, including in the study that I presented of the all oral version about how you can safely, slowly reduce the number of days in the post-remission setting and maintain efficacy. In the oral decitabine and venetoclax study, by cycle three, patients were receiving fewer than 20 days of venetoclax per cycle, but it was still 17, 18 days, not three or five. So the discussion with the clinicians is, be careful, don’t chop the dose down too much because we don’t have efficacy data for that, but to watch closely the blood counts and to try to mitigate myelosuppression by carefully, carefully reducing to, you know, you wanna get as many days in as possible, but without causing toxicity.

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