iwAL 2019 | Venetoclax-IDH inhibitor combination therapy for AML

Naval Daver, MD:            So there’s a number of new combinations in AML, and and the field is really moving at a breakneck speed. And, even in the big cancer centers where we’re leading these trials, we often have to be very swift on our feet and change the trial designs as we see data emerging. And you know, the era of the large multi-year phase threes has really become more and more restricted in the United States because of the pace of development. So, I think one of the drugs that is really pushing these combinations, and it’s kind of the, let’s say the backbone of many of these combinations is Venetoclax. So as many already know, the combination of azacitidine or decitabine with Venetoclax in the front line, elderly AML not fit for induction has shown blockbuster activity response rates of 71, 72% CR CRI median overall survival of 18 months and three years survival of more than 40% so not something we have never seen even close to an elderly AML.

Naval Daver, MD:            And this has led to the approval of that combination. But we think that there’s actually much more to the story with Venetoclax and so now we are looking specifically at three major combinations with Venetoclax, which are all early but the preclinical and the emerging clinical data looks very exciting. So one of them is combining Venetoclax with IDH inhibitors. So, one of my colleagues, Doctor Courtney Dinardo has worked extensively on IDH inhibitors. They’ve also worked closely with Steven Chan and others who did a lot of the preclinical work looking at potential approaches to developing synergy between Venetoclax and IDH inhibitors. And based on this they have developed two studies. One is with the IDH two inhibitor in combination Venetoclax and the others were the IDH one inhibitor in combination Venetoclax, the study that’s already enrolled a good number of patients is the one with the IDH one inhibitor, Ivosidenib with Venetoclax.

Naval Daver, MD:            This one will be presented at EHA and we are seeing some very striking activity, high response rates in excess of 70% in relapsed AML with IDH mutation. So I think that’ll be an important piece of data to look at, at EHA. We hope to start the IDH two combination soon as well. This will be multi-center and the whole goal. The goal is that if these therapies, the doublets without using chemotherapy and potentially even without using hypomethylating agents remain this effective, we could really start looking at an era where we will have oral targeted therapies in AML. We have an example of this, for example with [inaudible 00:02:24] arsenic without chemotherapy in APL and we think maybe this could happen with IDH, Venetoclax and the other approaches. Well for frontline patients maybe we will build ASA Venetoclax plus IDH inhibitor and that’s arm is actually also opening.

Naval Daver, MD:            So, a lot of people always ask me, you know, which would you use asa Venetoclax and asa IDH and we don’t think that this is a competition between the two. We actually think that ideally these can be used. Of course we have to find the right doses, the right schedule, interruptions, sequences, and that’s what these trials we’re looking at. But eventually I think if we can give them appropriately, we could really improve that three year survival from 35, 40% of ASA-vent, to maybe 70 80%.