SOHO 2026 | Lessons from Phase III ENHANCE: TP53, transplant, and MRD in future HR-MDS combination trials

We have essentially four, you know, large, you know, Phase III trials, three kind of agnostic to any subset that, as you said, have been negative and not just a little negative and kind of stone-cold negative from that, at least with VERONA and with ENHANCE. I think sabatolimab did have a trend that was intriguing. I think we’ve answered a couple of critical things. One is, I mean, we can accrue these trials. Actually, if anything, we could even accrue larger trials. I think could we accrue 1,000 patient high-risk MDS? I think the answer is yes. These trials accrued pretty rapidly even in the COVID paradigm. Most important is that P53 is its own set. So one of two things. You either run P53-specific trials, which we did prove we could do on ENHANCE-2, as well as our older APR trial, or the trial has to be powered to really like not include this group of patients. Because if you don’t have a signal there, then this, this unfortunately is up to one third of patients in our trials, maybe even higher. It was at 35% in ENHANCE. And actually, if you look at the subset, actually the wild type, it’s not that they did better, but they were kind of purely equal. But it was really the P53 mutant group that actually on the Phase III, which was different than our Phase U experience, did worse. So P53 really needs to be its own disease, its own trials. And again, if it has to be included, it really needs to be maybe powered to where we could still have a positive trial in the wild-type population from that perspective. So I think that’s most important is thinking about P53.

I think second is the transplant. So in ENHANCE, we had up patients, you know, going to transplant. And there was almost a doubling difference between the placebo arm and the investigational arm. In the STIMULUS, sabatolimab, only 8% went to allo. So it was like 32 versus 8. So 400% difference of a curative therapy cannot be a thing in frontline trials. So I think the question is like, if we were in VERONA as the allo, truly transplant eligible, two or three patients, like would the trial have been positive or not? Again, I don’t know. I think we’re interested actually in those subsets we still haven’t seen, but clearly like transplant, has major impact, had major impact, in ENHANCE as well. Of course, if you’re doing better, higher responses, maybe you get more people to allo. But still, transplant can cure people with refractory disease, what blast cutoff you need. There’s a lot of controversy. So I think we really have to run a fit trial. Like, hey, the goal is 75% of people going to transplant, or the goal is close to zero. Now, of course, it’s not going to be perfect, but I think we can’t just have it as whoever goes, and you can’t control it saying, hey, do you think somebody’s transplant eligible or not? That does not work as part of all of these trials. So I think, yeah, one P53, two is the transplant question. So for example, maybe frontline CPX could be a positive Phase III for high-risk MDS. The data from Paloma looked good. It actually builds on both data that we collaborated with Megan Jacoby at Wash U, as well as there’s another study that was done in France from that perspective. So I think those are probably the biggest things. I do think there’s more heterogeneity in MDS and whether or not blast numbers should impact trial accrual. I think that’s a separate question.

I think the third thing we learned from ENHANCE, so one is think about P53. Two is think about transplant. Three is MRD matters. So I think the coolest part of the paper, and this is in the supplement as well, is that if you achieve MRD negative, even with aza monotherapy, which people would say, hey, you don’t get MRD negative, it mattered. So in both arms, if you achieved MRD negativity, again, even with, let’s say, suboptimal therapies that we’re dealing with, that improved outcomes from that perspective. So I do think we should incorporate MRD by flow and then potentially by sequencing techniques in the future in all of our future prospective studies. This might further give us insight into how beneficial something is. And maybe this helps us determine in Phase IIs, not just response rates, but could MRD negative tied in with the duration of response? Could that be our go, no-go signal so that we don’t have more negative Phase III trials?

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