Promising Data for Pevonedistat in High-Risk MDS

Gail Roboz, MD: For TP53, in particular, I don't think we are- we haven't broken through the TP53 barrier yet. I don't know if Amy, you want to just mention for a second some of- there is some emerging data for Magrolimab which has a mechanism of action that I think people like to say don't eat me signal because it feels funny to be able to say that, but do you want to talk for a second? Are we close to cracking the TP53 net or do we have another minute?

Amy DeZern, M.D., M.H.S.: I think we might be, and you stole my thunder. I love to say don't eat me. Magrolimab is a really interesting drug and it's the first in class macrophage immune checkpoint inhibitor. It targets CD47, which is that don't eat me signal that's actually expressed in a lot of cancers but including AML. One of our colleagues Dr. Solomon presented it at Ash December past, some promising data that showed a focus on how Magrolimab might be just as good or even better in TP53 patients. It's not monotherapy. It's combined with azacytidine. I'll just mention that CD47 is on older, more mature red cells as well so there's an on-target early anemia when it gets dosed, but what the preliminary data looked like if I'm remembering and Rami, you can correct me, but the overall survival was a little longer in P53 wild-type patients, but it was more promising than we tend to see it over a year with the combination with Magrolimab in the TP53 mutated patients. That is a benefit that we are hoping to see for real extension of life there. I'm not sure it's going to be specifically for TP53 patients. I think it certainly treats all comers, but I'm hoping it is something that will be in our arsenal in the future that can augment the life of those patients with what is really the worst of the worst higher-risk disease.

Gail Roboz, MD: It's nice to see things coming up through the ranks. We have Venetoclax data emerging. We have Magro data emerging and another one that is kind of far along that we are waiting for definitive data is Pevonedistat. I was wondering, maybe we can have a couple of different comments on that. James, I don't know if you want to kick that off? Novel interesting mechanism of action with maturing data suggesting maybe we're onto something.

James Foran, MD: Yeah. I'll disclose, I've been an investigator for many years with Pevonedistat in AML and then in MDS. We've contributed to publications and contributed patients to studies. The mechanism of action is really interesting to me, kind of an upscale upstream proteasome inhibitor in a way, if you want to put it that way. It's called a Medaid inhibitor and a superficially higher response rate. A randomized phase 2 study in some high-risk MDS patients showed a signal of activity. The PIVOTAL trial has been completed. Accrual is completed to the enhanced study, and we'll have to wait and see. We will get some subset information on different mutation groups to know if there's a group that benefits more than others or whether it works overall. That's an area where we've contributed to and really looking forward to seeing trial results, to see if that's a step forward. I'm hoping it is. We definitely need to step forward.

Gail Roboz, MD: Azra, it seemed at least preliminarily that the additional other agents, when they're added to hypo methylators have not been totally easy actually. We've seen certainly with Venetoclax it may be fantastic at clearing the marrow, but there is myelosuppression. There have been toxicities at least preliminarily with the Pevonedistat. The toxicity profile looked pretty good. Would you think that if they're- again, they need to hit survival, they need to hit so we're looking for better responses with reasonable duration with longer survival, but do you have any sense of sort of from a toxicity perspective, maybe that would be a combinable agent if they're able to show those final outcome measures from the phase 3.

Azra Raza, MD: You mean the Venetoclax and HMA and Medaid inhibitor?

Gail Roboz, MD: I was talking more for the Pevonedistat. I think that's going to, I don't know, but I think those data might be sooner than the Venetoclax. I'm not exactly sure, but from a combined ability perspective, I thought that there was less Myelosuppression with the Pevonedistat.

Azra Raza, MD: Yeah. I agree. Especially, Gail, in this particular phase, the study that I'm looking at, I thought an interesting subgroup, and I would love for James to comment on it was the lower-risk patients who had bad mutations. Not just high-risk MDS but that group also benefited from this, whatever ubiquitination activity, this inhibition this has. Gail, I have to say that I'm not excited about any of these until really large phase 3 trial show an advantage in a blinded fashion simply because there is many a slip betwixt. We know that. Look what happened to the specific P53 inhibitor. That's not working. And something that we had no idea would work, like magrolimab, is working for patients. It just tells us that it's not a targeted treatment that's working, it's basically presence of p53 mutation is indicating a disease overall, which for some reason is more amenable towards immune manipulation rather than something else. Combining agents is a good idea because we didn't get the same until, we couldn't treat AML until we combined C and daunomycin, but it may be that in MDS, less is more. And we should never forget that. We are not going for cytotoxicity. We are not going for myelosuppression. We are not– You see, because it's not just one clone that has become abnormal like in AML. In this, it is one clone, but it is responsible for all of hematopoiesis now. When you try to wipe out a clone, you're wiping out all of hematopoiesis. I'm not in favor of any combination. And remember how excited we were about LEN and HMA combination to begin with and how that fell completely flat on its face. So no, I am not in favor, unless somebody shows me that in a Phase 3 there is more than 0.05 p-value and more than a 2.5-month improvement in survival.

Transcript Edited for Clarity