Use of APR-246 and Oral HMAs in AML

Harry P. Erba, MD, PhD: Eunice, you mentioned CC-486 [oral azacitidine]. This is the latest of the FDA approvals for our patients with acute myeloid leukemia [AML]. On September 1, 2020, the FDA approved oral azacitidine for adult patients who have acute myeloid leukemia in first complete remission [CR] or CRi [complete remission with incomplete hematologic recovery] after intensive induction therapy who have not undergone or were not candidates for, as you mentioned, curative therapy. What they meant by that was curative cellular therapy or allogeneic stem cell transplant.

That approval was based on the study meeting its primary end point of an improvement in median survival from 15 months with placebo up to 25 months’ median survival with oral azacitidine. However, it should be pointed out that, if you look at those Kaplan-Meier curves, by 48 months, or 4 years, they are coming together around 20%. I agree with you that we should still be thinking about transplant for these patients, but for those who are ineligible for transplant for whatever reason, oral azacitidine presents an option for them. You need to know how to manage the GI [gastrointestinal] toxicity, and you need to know how to manage some of the myelosuppression. You can get these patients through this therapy, and they may benefit from an improvement in survival by delaying relapse.

At last year’s ASH [American Society for Hematology] Annual Meeting, our colleague from New York, Gail Roboz, presented data on the MRD [minimal residual disease] assessment. Around 45% of patients were MRD positive by flow cytometry prior to going on the study where they were then randomized between oral azacitidine and placebo. The benefit of oral azacitidine was seen in that group as well as the MRD-negative patients, as you mentioned, Eunice. On top of that, some of those MRD-positive patients became MRD negative over time. Whether they also got well enough to undergo transplant would be an important issue. It may be a great bridge to transplant, but we have no data looking at that. This is another therapeutic option for our patients who are not able to proceed to allogeneic transplant in first remission.

One of the challenges we have is getting patients with AML with TP53 mutations to transplant. Sasha, do you want to talk to us about APR-246?

Alexander E. Perl, MD, MS: Sure. It is an interesting drug. It is perhaps unique among the therapeutic armamentarium in terms of being a drug that is being developed not just for TP53 mutations but also to target TP53 through its effects on unfolding that protein/ At least that is the purported mechanism of action. It is a drug that has been evaluated primarily in the context of hypomethylating agent [HMA] activity in TP53-mutated MDS [myelodysplastic syndrome] and AML. In reality, because there is such a tight correlation between MDS and AML with that mutation—it is a spectrum of the same disease—the response rates are seen across the spectrum in terms of both MDS and AML responses with this new drug.

It was evaluated in combination with HMA in a study presented at EHA [European Hematology Association] Congress, but there was no update at ASH last year. A treatment-naïve or HMA-naïve population that was of median age in their mid-70s was treated on a study combining APR-246 with HMA, and the phase 3 of this approach has completed enrollment. The presented data showed a response rate in terms of CR and CRi that exceeded 50%. I believe it was 64% for the entire cohort, about two-thirds of whom had MDS but a third of whom had AML. Here, AML was defined by 30% blasts, not 20%, so it has a high response rate in this population, and it is certainly in the range that we would expect would be higher than HMA alone. This is promising going into the phase 3 setting, and we look forward to those data in the future.

There have been some toxicities with this drug, including neurotoxicity from it. It is an IV [intravenous] infusion. It takes a prolonged infusion, but the mechanics of it do not limit its administration in the outpatient setting. It is an interesting compound going forward.

Harry P. Erba, MD, PhD: I agree. What I love about the ASH meeting and these recaps with my colleagues is that I am learning as we speak. I have recently learned—within the last few seconds—that APR-246 is going to be called eprenetapopt.

Alexander E. Perl, MD, MS: I am glad you said that and not me because I am sure I would have mispronounced it.

Harry P. Erba, MD, PhD: It will be APR-246 for a while longer.

Alexander E. Perl, MD, MS: Forever.

Transcript Edited for Clarity

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