Episode 57: The KOMET-007 Trial

Dr. Amer Zeidan joins the Healthcare Unfiltered EXPRESS to discuss the recently published KOMET-007 trial, which made its way to print in Blood. Dr. Zeidan discusses how Menin inhibitors are transforming how we approach AML like no other therapies before. What does the future hold and how will the results of this trial affect therapy? The KOMET-007 trial is a Phase 1/2 clinical study evaluating the targeted Menin inhibitor ziftomenib in combination with standard-of-care chemotherapies for acute myeloid leukemia (AML) patients with NPM1 mutations or KMT2A rearrangements. 

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Transcript

SPEAKER_00 0:01

Welcome to the Healthcare Unfiltered Express, where I conduct short video interviews packed with relevant and timely information that you cannot miss. So sit back and enjoy the show. Well, he's back on the show. Amer, I always appreciate you taking time of your busy schedule to be on uh Healthcare Unfiltered Express edition this time. Thank you so much for coming on.

SPEAKER_01 0:28

Yeah, thank you so much for the invitation. Always one of my favorite podcasts, and I always love coming here.

SPEAKER_00 0:34

Thank you so much, Amir. And just a reminder for folks who are listening or uh watching this on YouTube, uh, where you work and what you do.

SPEAKER_01 0:42

Yeah, so I'm the chief of the division of hematologic magnancies at Yale University and a professor of medicine here at Yale as well. I focus primarily on acute myeloid leukemia and myelodysplastic syndromes and uh do both clinical and translational research in both of these areas.

SPEAKER_00 0:59

And really the reason I asked you to come on the show was uh uh in healthcare on filtered express, we focus on one topic, one paper, just basically to try to get the maximum return on investment for viewers and listeners. And I came across the Comet uh or Comet 007 trial that was published recently in Blood uh uh discussing the value of adding a menon inhibitor to uh vinitoclax and azacytadine. Let's just start a little bit. Tell us a bit on uh menon inhibitors and why they're important and and where zoftimine fits in, which is the drug that was used in this trial.

SPEAKER_01 1:40

Yeah, so men inhibitors I think are um equivalently the most promising and the most exciting drugs in acute myeloid leukemia these days. Um and also part of I think the nice story here is that how they were rationally kind of designed. So we we knew for a long time that certain types of leukemia have activation of a pathway called hox A9 slash mees, bees1. And this pathway is important in the differentiation of uh hematopoietic cells. So uh in certain types of leukemias, which are clearly characterized by a block in differentiation and excessive proliferation of the cells, this pathway has been upregulated. And then it was discovered that um part of the upregulation, or many of those patients who have upregulation of this pathway have certain genetic alterations. One of them was MLL, or what has been renamed as KMT2 range leukemia, and that's around 5 to 10 percent of acute myeloid leukemia, but also happens in ALL and um in pediatric ALL as well. And then MPM1, which is a significant number of leukemia. So it was actually interesting because you have two very distinct genetic alterations, but they diverge or converge, sorry, on one um kind of one common uh pathogenic um mechanism. And then subsequently it was found that beyond these two specific alterations, there are other rare alterations such as NUB 98, for example, and other translocations that are also associated with increased expression of this pathway. And uh subsequent to this, it was uh discovered that uh men men, which is uh just to remind the audience, is actually a scaffold protein. So this is a protein that's expressed uh in uh in the nucleus. What it the way it functions is like a scaffold where other proteins are uh uh are kind of stuck on it and it goes to the chromatin, so it affects the transcription of uh important uh factors in differentiation um and other functions within uh the cell. And what was discovered is that when you have MLL rearrangement, and there are more than 100 gene partners with the MLL genes. So when you have those rearrangements, this leads to um a uh disruption of this pathway. So you have increased expression of hox A9 and MIS1 that leads to uh leukemia, but also the same thing has been seen with the MPM1 uh mutations, and subsequently uh those menon inhibitors were developed, so they disrupt the interaction between menon and KMT2A. And when you disrupt this interaction, uh this leads to uh reversal of this process, so this leads to differentiation of the cells, which by the way can also lead to what we call differentiation syndrome, but as a as an efficacy signal, it leads to differentiation of the cells and um uh responses. And this was seen in animal models and subsequently was taken to the clinic. And this story went very quickly from a lab-nice translational story to full approval, where we had the first drug approved, which was rebiomineb, the first oral uh menin inhibitor. This was approved initially for MLL rearranged leukemia, and subsequently, both zephtominib and another, sorry, both rebiominib and uh kind of second-in-class agent called zephtominib were both approved end of last year on October and November 2025 for MPM1 uh mutated AML as well. So this was uh kind of the beginning, I think, of a very um uh important era because now there's a number of other drugs. So those are the two that are approved, but there's a number of other ones, such as Pleximinib, Insominib, um, uh, and others that are still in early clinical development.

SPEAKER_00 5:29

This is a great overview. Uh Zeftuminib is the drug that was in comet 007. Uh, a little bit about the zeftuminib efficacy and so on, and then we delve into the study and what happened in combination between zeftunib and and and azaven.

SPEAKER_01 5:47

Yeah, so zeftuminib, as I mentioned, was just approved end of 2025 as a monotherapy. So the initial approval was with it as a monotherapy. And by the way, it's a pill, it's taken once a day. It has a low chance of drug interactions with azoles and antifungals, which we use quite a bit in in AML. So it's relatively easy to give, which is a differentiator from raviolomineib, which is given twice a day, and it has a number of drug interactions that require adjustment of the dose. Um, so zeptomineb was initially approved based on the study called the Comet 001. Uh, this was a single arm, but a large, a large phase 1 slash two uh study with the drug as a monotherapy, and it showed complete responses. Again, you are talking about multi-relapsed leukemia after numbers of line of treatment, some of them then exposed, some of them after transplant, relapse, which all of these are very kind of uh difficult situations. All of them had to be MPM1 mutated. So the approval for uh zephtominib is an MPM1 mutated refractory lapse leukemia. And what the drug showed is around uh complete response slash complete response with partial count recovery in the range of 25%. Uh, there were also other benefits such as transhusion independence, the durability uh of the response was in the range of four to six months, and the survival was around six months. So um the data looked good. Uh, that this led to the approval, but uh I think uh in in the relapse refractory setting, it's always very challenging to see the full benefit of the drug. So there was a lot of interest in trying to move the drug in the front line and combine it with other effective drugs. This is a paradigm that worked very well on oncology to combine drugs that have efficacy because this way you have synergistic uh impact and you overcome clinical uh or resistance mechanisms that might evolve later. So, this is where this trial that you just mentioned, called the Comet 007, uh, came around. So the COMIT 007 has actually a number of trials kind of put in one, so multiple arms. So one arm looked at combining um zeptimonib with the standard chemotherapy, intensive chemotherapy, 7 plus 3 in patients who are fit for intensive chemotherapy. And again, all of those patients had to be MPM1 or KMT2 area arranged uh to go on the study. The second arm of this study was combining zephtominib with ezavin, which is the standard approved treatment for unfit patients. However, uh to get to that point, you had to do the dose escalation, and part of the discussions with the regulators uh because the combination was still being discovered kind of in terms of its safety, we had to do that in refractory lapse patients. So the initial dose escalation was in relapse refractory patients, but once we have done finished that part, we went to the frontline uh A-s of N combination. So, what was just published in blood was that part, which is uh dose escalation uh in the relapse refractory uh patients uh uh in combination with A-s of N. The other two parts, which we I'm happy to talk about later in the in the in the talk, are still ongoing, and there has been a presentation of this data in the frontline setting in uh in a number of congresses, including uh one that we are doing actually next week in here. So it's quite exciting times.

SPEAKER_00 8:59

Yeah, and we're taping this for listeners and viewers. We're tipping this before before EHA, and it's likely going to air after EHA, just for folks who are watching and listening. So, whatever you can share from this, that's always welcome. But the Comet 007, the paper and blood specifically focused on relapse refractory, NPM1, AML patients. And I I was reading that the phase 1A portion looked at 200, 400, 600 milligrams, and then the expansion cohort was the 600 milligram. Um what what uh um the Ven Aza was chosen because this is the most commonly used uh in the community. Is that why this particular uh arm was chosen?

SPEAKER_01 9:41

Uh yeah, this actually again is a very good question. So there are a number of reasons for this. I think them the most uh the most uh kind of uh strongest reason is what you mentioned is because Azevin is a standard of care drug in the frontline setting. However, we use it very often in the second line setting as a salvage therapy for patients who have not received it. For example, when you give it to uh patients who get intensive chemotherapy uh and then they relapse, we often will use Azevin, although it's not approved in that setting, but it's it has activity. We actually published a large series uh from Yale and other centers have done so where we are showing complete responses um, you know, in uh in a good number of those uh patients. So people are often using Azevin in that setting. So the practical question became is if you have a patient, let's say, who has MPM1 AML and got 7 plus 3 and then they relapse, would you give them a min inhibitor because they are now approved in that setting, or would you give them Azevin? And you know, the always the best answer, my opinion, is you know, combine all of your effective drugs together. And this is what was done here is that uh zephtominib was added to ace of in. And as you mentioned, this went through a dose escalation phase for the zephtominab 200, 400, and 600. And eventually we settled down on the dose of 600, which by the way is the dose that's approved as monotherapy, and also is the dose that is in all these uh ongoing trials in the front line, including, by the way, I didn't mention that, but there's already ongoing phree now, um, looking at the combinations in the frontline uh setting as well. All of them are using 600. Uh so 600 milligram is the dose that was uh chosen for uh expansion.

SPEAKER_00 11:24

And I like this trial because there's some pragmatism to it, because that's what folks are using in the community, Ben is uh so you're really adding to it. So tell us about the results. What did the trial show uh in terms of response, duration of response? And and I saw a lot of comments on minimal residual disease as well.

SPEAKER_01 11:42

Yeah, so I think the data kind of looked uh looked quite good in that context. Just to remind people, like you know, refractory lapse AML is certainly a very challenging situation. The only way you can cure these patients with a bone marrow transplant, but sometimes the patient has already relapsed after transplant or they cannot go to transplant. So generally the survival in this patient population is not gonna look very good, even with very good drugs. But uh you you certainly uh what we saw within the context of the of the trial is that the combination was well tolerated. We did not see additive toxicity by adding zeftominib on top of azabin. The most common toxicities are what you typically see with azavin, which are primarily um uh myelosuppression and infections. Uh, one important point, by the way, I didn't mention that uh um kind of at the beginning with that, but one of the side effects of zephtomineb uh and all mini inhibitors, it's a class side effect, is differentiation syndrome, which can happen, can be severe, uh, it has to be closely monitored, you have to interrupt the drug, give steroid, supported care, etc. And the reason why I mentioned this is that we uh the combinations are good because of the synergy and the efficacy, but also because they minimize the risk of differentiation syndrome, because you're already giving concomitant chemotherapy, which will reduce the chance. So this um so what was expected and what we saw is that the risk of differentiation syndrome, the severe differentiation syndrome, was actually quite low. This is what we saw here. Uh, there were only two cases out of uh two cases of grade three and higher out of like I think 67 patients who were uh treated on the trial. So the number of patients was quite um uh uh was quite low and generally uh well um well managed, like completely reversed. UTC prolongation is not a big issue, but it certainly can be seen because of the concomitant minutes that we give for those patients. When you think about the efficacy front, so I think it's important to think of efficacy in terms of what we call um uh venetoclax naive versus venetoclax exposed. Because as I mentioned, for me, the uh most important patients for this regimen would be patients who have got an intensive chemo and relapse. So they have not seen Ven, they have not seen HMA, they have not seen Zephtomina. In those patients, the complete response rate uh composite CR was around 70%, was very very high rate of response. Um, if you had prior VIN exposure, it still works, but the activity becomes lower. It's around um uh 25% composite CR in VIN prior vein exposure, uh, which again is not surprising. And we know that patients who have VIN uh refractory disease have very poor prognosis in the range of four months. Um, so I think on that front, again, it looks um it looks the regimen is quite active. I think where we need to do better is in terms of how do we improve the durability. The median duration of response in this trial was eight and a half months, which again in the context of relapse refractory leukemia is is good because those patients do poorly, but we really want something longer. And the median overall survival was not reached um at the time of the kind of um uh publication. So I think one of the things we wanna um we wanna think about uh and you alluded to is the MRD negativity. So we know that getting to deeper responses also correlates with better activity for patients. Uh, and we saw a good number of MRD uh negativity in in this patient um uh population. If I recall um the number exactly, I think it was in the range of 50 um percent in that that and it depended on on vinetochlax exposure or not.

SPEAKER_00 15:16

I was gonna ask you the the um the I mean the the side effects seem to be tolerable. The differentiation syndrome was not really as as you know as as bad as thought. But also in this patient population that you guys published in blood, there were patients who have failed transplantation to your earlier point. Some of these patients on the study were patients who had failed transplantation.

SPEAKER_01 15:39

100%. So many of the patients had prior vein exposure, many of them had multiple lines of therapy, and many of them also had prior transplant. And the reason why this is important to put in context is when people look at the duration of the CR or the response, and they say, well, it's only eight months or the uh you know, or the or the fact that uh 25% only responded after pre-air vent therapy. You have to look at that in the context of how heavily this patient population has been pre-treated. For me, this trial, again, these are good results, but for me, this was all about making, and the reason why we did this actually, again, this was a dose escalation to find the right dose to go to the front line. So the whole idea was to transition this to the front line, which we already did. So I think we proved the efficacy, we proved the safety in the second line. So we had to go to the front line where we are already seeing uh CR rate over than 70%, and uh, you know, very durable responses and very good safety profile. But practically, the reason, and that's part of the reason why we publish this now, is because of the practical question: can you combine these drugs safely? And should you choose ziphtomilib or azeven? And this way we are providing evidence, I think, for people that they can do the triplets. Uh, so this way, uh, even again, technically it's not approved, but you have supportive data about the safety and the efficacy of the triplet for those patients.

SPEAKER_00 17:03

Absolutely. This was really excellent. Is there anything I should have asked you on this trial that I completely forgot?

SPEAKER_01 17:10

No, I I think you covered it quite uh quite a bit, but uh I would just like add uh, you know, maybe a teaser, but uh to kind of uh think about uh the next steps is as I mentioned, this move to the frontline sitting, both in combination with AZM, but also in combination with 7 plus 3. And we are seeing, I think, really outstanding uh results. The response rates uh are in over 70 percent completely. You are talking here about completely CR. The overall response rate was in the range of 90 um, and we still too early to see the durability, but many of the patients are in durable uh responses. We are gonna see this as it matures over time. But because of these encouraging data, we already have uh a randomized phase three trial uh called the Comet 017, which is randomizing. So this is two in one kind of a trial. So it has uh it's one protocol but has two large registrational intent trials. One is going with for A7 plus minus ZIF2, and the other one is seven plus three plus minus ZIF2, depending on whether the patient can be fit or not fit. And uh, you know, I I um I have to give like the sponsor and uh FDA credit because this is a this is a design actually I strongly uh uh kind of advocated for and eventually went through because it's very convenient uh from an operational point of view to have both protocols or both trials in one protocol, but also from a patient-centric um angle, because this way you can choose the right trial for the patient based on their fitness rather than having to kind of have two separate uh trials and two separate uh protocols. And the last thing I would add is that, as I mentioned, there are other drugs that are uh other goodman inhibitors that are also being tested. So there are ongoing phase three trials with the raviominip, they are ongoing phase three trials with uh blexeminip. There are also intensive chemo and seven and a7 combinations with uh with both of those drugs, raviominip and blexeminib. So I believe this is the paper you we were talking about today, is the first published paper uh as a combination. Uh, but there has been data that has been presented in combination for the other drugs, and I'm sure they will be published in the near future. So, overall, I think very good news for the field, and we continue to be very excited about what's to come.

SPEAKER_00 19:22

Okay, well, thank you so much for joining me, Amer. Before I let you go, the million-dollar question who's going to win the World Cup, and then I'll let you go. Come on, on the record, who do you predict? If I'm gonna have to guess, I would say probably France, but we'll see. Me too. I think it's gonna be France or the Netherlands. Dr. Amer Zidane on Healthcare Unfiltered, thank you so much for coming on. Yeah, my pleasure. Thank you for listening to this edition of the Healthcare Unfiltered Express. Until next time, take care.