Guillermo Garcia-Manero, MD: We really need to improve everything we do for our patients with myelodysplastic syndrome [MDS]. But we could think about some specific problems. For sure we need new therapies up front in high-risk disease that [will] improve survival. We need better therapies for patients with TP53-mutated disease. We need to develop some strategies post-transplant for those patients who are at higher risk of relapse post-transplantation. Then finally perhaps we need better, actually, any therapy, I should say, for patients with this so-called hypomethylating agent [HMA] failure situation, meaning patients who have received a drug like azacitidine or decitabine and are either not benefiting or losing benefit. Those are a few of the examples where I think we could do much better. But there are many more where we could improve.

The ASCERTAIN trial was the study I led, that led to the approval of oral decitabine with cedazuridine in MDS in the United States. As you know, the 2 hypomethylating agents that we had prior to this compound were decitabine and azacitidine. They’re both either IV [intravenous] or subcutaneous, and they require chronic administration. For many years we wanted to have an oral version of this because this would make the lives of our patients significantly easier. I worked to develop both of them, the oral azacitidine and oral decitabine. The oral decitabine is combined with a drug known as cedazuridine, which is what we call a cytidine deaminase inhibitor. It is an enzyme that basically inhibits the absorption of drugs like decitabine and azacitidine through the GI [gastrointestinal] tract and maybe the liver. We did a number of phase 1/2 trials combining the decitabine with cedazuridine until we got the right dose, which is 35 mg of decitabine, and 100 mg of cedazuridine. Then we performed a phase 2 study where we looked at the PK/PD [pharmacokinetic/pharmacodynamic] profile of this drug, which looked very similar to what we knew from IV decitabine.

Then we launched this randomized study known as the ASCERTAIN trial. This study led to the approval of oral decitabine with cedazuridine in the United States. It’s a randomized study looking at 2 sequences of giving IV vs oral decitabine. This design allowed for intrapatient evaluation. We found that the PK, the pharmacokinetic profile, was [nearly] identical, 99%, almost perfect. Also, the pharmacodynamic end points, for instance looking at global DNA methylation, were identical. This means basically that for those patients and doctors who use decitabine, you could switch to an oral formulation without having to inject that. That’s a really important issue.

The study is being reviewed for publication right now. It was presented at ASH [American Society of Hematology annual meeting] a couple of years ago. The approval of this drug was [about] 2 years ago. Basically, it now allows for an opportunity to look at a specific subset of patients. One of the critical points, as we started the discussion a few minutes ago, is in this group of patients with TP53-mutated disease. Traditionally we thought this was around 8% to 10% of the patients, but it turns out that in more recent analysis, at least at [The University of Texas] MD Anderson [Cancer Center], we see 30% to 40% of our patients have this particular alteration. And what we know of this is that it is associated with a very poor prognosis. Right now this is probably one of the most complex groups of patients to treat.

Michael Savona, [MD,] who was the first author of the presentation, and myself as the senior author, evaluated the impact of this mutation in this cohort of patients. The beauty of this is that this…done in the specific context of a prospective clinical trial. The data are interesting. What they show is that, perhaps higher than expected, around a third of these patients in the ASCERTAIN trial were mutated for TP53. This was associated with a worse outcome than for those who did not have the mutation. Then we performed a secondary analysis where there is now evidence that not every TP53 mutation is the same. For instance, work by…doctors in New York showed a couple of years ago that if you have what they refer to as a biallelic mutation, meaning that the 2 alleles of the gene are altered, then the outcome is significantly worse. We then basically performed an analysis looking at those that were mutated and divided those that were monoallelic vs biallelic, and again we showed, similar to what had been proposed by [Elsa] Bernard, [PhD], that those with biallelic mutations did worse.

But what was interesting from this is that the survivals that we have shown for the TP53 mutated, the monoallelic, and the biallelic, although they were inferior to the [survival rates for] unmutated [patients], were actually superior to what had been reported prior in other studies with hypomethylating agents, or in studies looking at this particular mutation in another clinical trial context. For instance, the survival of biallelic mutated patients here was around 13 months. That is greater than what you would expect from other studies where it’s around 8 months. The survival of those patients with a monoallelic mutation was much better than expected, which traditionally has been around 11 months or so. Here we showed that this was way above that.

So the question is, why is a drug like oral decitabine plus cedazuridine associated with what looks like better outcomes compared to what was expected? Of course, this is not a randomized study in TP53-mutated patients comparing oral decitabine vs some other HMA or another drug. But I think in the context of a prospective randomized study, for sure it doesn’t look like this is inferior to anything we’ve done before. It may actually be superior. And the question is why? How do we test this, and how do we move forward? It’s an intriguing observation from this trial.

Transcript edited for clarity.