Promising Early Results from Menin Inhibitors for Treating AML | Harry Erba, MD | #ASH24

Hi, I'm Harry Erba from the Duke Cancer Institute in Durham, North Carolina. At this year's ASH meeting, there was an entire oral session focused on the development of Menin inhibitors. Menin is a key player in the pathogenesis of NPM1 mutated AML and AMLs or ALLs with a KMT2A rearrangement. The remission rates are quite high in both groups with standard intensive chemotherapy. However, relapses still occur, and although NPM1 is considered favorable risk, that's only relative to the very unfavorable risk of other forms of AML. So a lot needs to be done for patients with NPM1 mutated disease and especially KMT2A rearrange disease, where the relapse rates are very high after intensive chemotherapy and even after allogeneic transplant. The Menin inhibitors target the interaction between Menin and KMT2A and have been shown as single agents to be active. What I'll discuss next are two of the drugs that I've been involved in with. The first, Zifto-Menin. Zifto-Menin has single agent activity in NPM1 mutated and KMT2A rearrange disease. What was presented by Amir Zaidin at the symposium this year was the early results of our phase study where we're combining Zifto-Menin with 7-in-3 intensive chemotherapy for patients with newly diagnosed NPM1 mutated disease or KMT2A rearrange disease. In our group of patients who received Zifto-Menin at three different doses, 200, 400, or 600, in addition to 7-in-3, the complete remission rate was 100%. And these are durable remissions. In the KMT2A rearrange patients, the remission rates were not quite as high, but still around 85 to 90% in the KMT2A rearrange. What makes the NPM1 data so interesting is that we were required in the study to only start our phase 1b with patients with NPM1 mutated disease who have a higher risk of relapse. And so we focused on patients over the age of 60, those with therapy-related AML, and those with cytogenetic-related mutations or high-risk cytogenetics, and still saw 100% response rate. Out of all these patients, we saw one case of differentiation syndrome that was manageable. There was no indication of QT prolongation, and we haven't seen any major drug-drug interactions, especially no interactions with CYP3A4 inhibitors such as post-econazole. The other drug that I can talk about as an investigator is Enzomenin. Now Enzomenin is a little bit different. Enzomenin was really very carefully and rationally designed not only to inhibit the binding of menin to KMT2A, but to have the properties of a drug that would decrease its volume of distribution and increase its lipophilicity, its basicity, features that are important for the activity of the drug. So a little bit different than the other three drugs that were presented at the meeting. What we presented here was our dose optimization. We are studying 200 milligrams twice daily, 300 milligrams twice daily, or 400 milligrams twice daily. For this Congress, we only had the data so far on the 200 and 300 milligram twice daily doses. In patients with a KMT2A rearrangement, the response rate in those patients who got 300 milligrams twice daily was 40%. In patients with NPM1 mutation, there didn't seem to be a response, dose response effect. So if you just include all the 200 and 300 milligram twice daily patients, the CR-CRH rate was 47%, one of the highest that we've seen with a single agent inhibitor. We did see differentiation syndrome. None of these patients needed to go to the ICU. They were managed with steroids. There was no prophylaxis. There was no ramp up of the drug, but the differentiation syndrome was able to be treated successfully with the use of corticosteroids and close hemodynamic monitoring. We also did not see significant QT prolongation. And finally, in the study, we were evaluating doses of enzomentib with or without strong CIF3A4 inhibitors with or without azoles, in other words. And there again, we saw no effect of the azoles on the pharmacokinetics of the enzomentib. Finally, we could correlate the responses with decreases in HoxA9 and MIS1 expression and increases in CD11B expression on cells with differentiation. And we're looking forward to now the 400 milligrams twice daily dose, getting more information on that cohort and bringing that drug into combinations with ACEVN and 7 and 3.