IDH1/2 Inhibitors for AML

Mark J. Levis, MD, PhD: Dan, you published on newly diagnosed patients getting enasidenib. Gail did publish the single-agent IVO [ivosidenib]. Tell us about enasidenib there.

Daniel Pollyea, MD, MS: Yeah. You know, very similar experience, very similar numbers, you know, patients included in that study. Similar sort of a design, in which the patients really came out of the original phase 1 in an arm of patients who had no prior therapy. And very similar outcomes, really, with respect to response rates and survival. So no big surprise there.

Harry Paul Erba, MD, PhD: And the responses with both IDH inhibitors seemed to be higher with combination with an HMA [hypomethylating agent] than VEN [venetoclax] alone. So there seems to be something there with that combination in the relapsed/refractory setting and in the newly diagnosed patient population. But I guess 1 of the most interesting things I saw at EHA [European Hematology Association] and ASCO [American Society of Clinical Oncology] was Dr Courtney DiNardo’s presentation on the randomized phase 2 of AZA [azacitidine] alone versus AZA and enasidenib. Higher response rates, but no difference in survival. Getting at what Gail was talking about, we’re starting to see some studies there. These patients are having longer survival than what we expect and have seen before.

Gail J. Roboz, MD: I’ll tell you, though, we haven’t done a good job with the super responders also. And, I mean, Dan and I have been looking at this in some of the data sets. So I actually have on the ENA [enasidenib] single agent, I have the person who would be absolutely the longest. I mean, this is an older patient who was 71. I forget exactly how old he was when he initially went on the trial, was told, “Forget it,” you know, nothing. Five years on single-agent ENA, and now back in remission in a hot minute on AZA/VEN when he relapsed. But the question is: How do we pick; how could we pick the patients who were destined to be those super responders? And this is single-agent initial therapy. So even though you’re absolutely right that the response rates that were just presented for the ENA/AZA were higher, the question is: Some of these patients actually can get single-agent IVO or single-agent ENA and live for a long time on it, but how do we pick them out?

The statement that you were getting to that we’re just getting very good at keeping people alive for longer on azacitidine: I think that that should still be used. Keeping people alive for longer is good. But I absolutely believe that if we could ever study the quality of life, being in remission is better; it has to be better.

Harry Paul Erba, MD, PhD: I agree. Amir?

Amir Fathi, MD: I just wanted to bring up a couple of points that I think are pretty important. One is that if you’re alluding to the abstract presentation from ASCO, I think you’re talking about the one that had 100-something patients who were randomized 2:1. I think we have to keep 68 in 1 arm, 30 patients in the other. The overall survival was, I think, 20 months or 22 months, something like that.

Harry Paul Erba, MD, PhD: Yes, 22 months.

Amir Fathi, MD: So, you know, this is not a randomized phase 3 study; we cannot assess, in my view, survival advantage in such a study. And so I worry a little bit about drawing conclusions from that. I do think that HMA plus IDH inhibitor is better tolerated than HMA/VEN, so I agree with Mark. And there are certain patients in whom HMA/IDH inhibitor is the better approach.

But all else being equal, I like to keep my IDH inhibitors in my back pocket because they provide a response rate that approximates relatively the response rate you get in the up-front setting. Meaning the relapsed/refractory patients had a response rate that approximates as monotherapy what you would get in the up-front setting. You know, somewhere in that overall response of 40% to 45%, complete response of around 20% to 25%. That’s what we have generally seen roughly in patients. And because HMA/VEN has such a high response rate, I generally in the younger patient, or the patient who I think can tolerate HMA/VEN, generally go with that first and keep the IDH inhibitor in my back pocket. On occasion, however, if I’m worried about whether a patient may tolerate HMA/IDH inhibitor better, I generally go with that. I’d like to have options so that I can prolong a patient’s survival with sequential therapy. There’s no data, obviously, to guide that, but that’s just been my general approach with these patients.

Harry Paul Erba, MD, PhD: When considering how to sequence these agents, HMA/venetoclax versus an IDH inhibitor, let’s remember that the labeled indication for venetoclax is in the treatment-naive older, unfit AML [acute myeloid leukemia] patient. Whereas the labeled indications for the IDH inhibitors were initially, at least, in relapsed/refractory; now, ivosidenib is approved also in the treatment-naїve patient, but if you sequence it with venetoclax first and then the IDH inhibitors, you don’t have to worry about the opposite situation, having to get approval for venetoclax. Having said that, I think most of us on this panel haven’t had much difficulty getting these medications for our patients with AML if they need it. But it is something to consider in terms of the sequencing.

Transcript Edited for Clarity