Oral Hypomethylating Agent Regimen Approved for MDS Improves Outpatient Treatment Options

Guillermo Garcia-Manero, MD

In July 2020, the FDA granted approval to the combination of oral decitabine and cedazuridine (Inqovi) as treatment of adult patients with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia, based on the positive findings from the phase 3 ASCERTAIN clinical trial. The indications for this approval include patients with previously treated or untreated de novo and secondary MDS and patients with intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.

The recommended dose for the approval is 1 tablet of 35 mg decitabine plus 100 mg of cedazuridine administered orally on days 1 through 5 of each 28-day cycle. Overall, the use of this oral version of decitabine compared well with the intravenous (IV) version of the drug. This is an exciting treatment option for patients with MDS as they no longer have to stay in the clinic for extended periods of time for treatment. This treatment can now be given orally in the outpatient setting.

According to the findings from the ASCERTAIN clinical trial, which was a multicenter, open-label, crossover study, the oral regimen had no new safety signals compared with the IV version, and it appeared to be safe as treatment of patients with MDS and acute myeloid leukemia (AML).

In an interview with Targeted Oncology, Guillermo Garcia-Manero, MD, professor and chief of Section of Myelodysplastic Syndromes, Department of Leukemia at The University of Texas MD Anderson Cancer Center, and principal investigator of the ASCERTAIN trial, discussed the FDA’s recent approval of oral decitabine and cedazuridine as treatment of patients with MDS and the data that supported this decision.

TARGETED ONCOLOGY: Before we get into the treatment regimen and this trial, could you discuss what the prognosis looks like for these patients with MDS and the treatment options prior to the FDA's recent approval?

Garcia-Manero: MDS refers to a very heterogeneous group of patients, so there are patients with lower-risk and higher-risk disease. In 2020, we divide these patients based on their age, comorbidities, cytogenetic alterations, and molecular alterations, so this is very different than 20 years ago when we had no compounds for patients with MDS. In general, the majority of patients with intermediate- to high-risk MDS, globally, not only in the United States, are treated with a hypomethylating agent (HMA), and there are 2 of these compounds. One is called decitabine, and the other one is called azacitidine. These drugs are given either intravenously (IV) or subcutaneously, and 1 thing that we learned early from the original experience with this compound is that they require very lengthy chronic treatments, meaning 5 to 7 days every month for as long as these compounds work. This is good news as it could be used for many years. This means that these patients need to stay in a hospital or clinic facility several days every month for a prolonged period of the rest of their life. We have had drugs, similar or hopefully better than the IV or subcutaneous HMAs, that we deliver as an oral drug, and this would be a major benefit for our patients. This is something that we and the patients have been hoping for now for 10 to 15 years.

TARGETED ONCOLOGY: Looking at the phase 3 ASCERTAIN trial, what was the rationale for evaluating this combination of agents as treatment for these patients?

Garcia-Manero: For years actually, multiple groups have tried to design ways to deliver these compounds orally. I'm talking about drugs like azacitidine and decitabine, but the problem is that there is an enzyme in our bodies called cytidine deaminase that has the capacity to destroy these drugs if you take them orally. What the investigators have been asked to do was to develop a combination where you administered the oral decitabine, in this case, together with a second compound that somehow inhibits this enzymatic activity.

This has been a project that has lasted close to 6 years where first, we performed phase 1 trials of this combination trying to find the proper ratio of decitabine with these inhibitors to attempt to get what would be the perfect molecular ratio of these 2 drugs, so we could achieve a pharmacokinetic (PK) profile that is similar, if not identical, to that of IV decitabine. It’s not that you're giving 2 drugs, per se, but you're giving 1 drug, decitabine, and a second drug that allows the absorption of this compound to levels that are what you see in the clinic with IV decitabine.

In that context, the phase 3 ASCERTAIN trial was designed specifically to answer this question. What we did is we randomized patients into 2 different sequences, and this has been important because patients received 1 month of the IV decitabine on this trial, followed by the oral version in the doublet, or vice versa, they could start with the oral, followed by the IV. The idea here actually was to compare the pharmacokinetic profile. I think it shows how focused we were on the particular end point, that was basically to demonstrate that the PK profile of the oral version of decitabine together with the cytidine deaminase inhibitor provided a PK profile similar to IV decitabine, and the data that we presented at this past ASH suggested that we achieved that, that indeed both drugs are virtually identical. It's not that they are similar, but they are virtually identical in terms of their pharmacological profile. That's really important because it suggests then that you can replace IV decitabine for the oral compound.

TARGETED ONCOLOGY: Could you elaborate on the findings from this study?

Garcia-Manero: These HMAs induce something called DNA methylation, which is something that a lot of groups have studied and worked on for many years. There are assays to look at the global impact on methylation of this compound, so that is another very important biomarker because in this particular clinical trial, we also measured global levels of methylation with a particular assay to show, again, the dynamics of methylation were identical between the IV form and the oral compound that we were developing.

We don't have enough follow up in this particular trial to really say if the responses are higher or lower, but the reality is that from prior studies and this paper, we see that the clinical activity of the compound is also what you will expect from IV decitabine in this group of patients. This is a major breakthrough for us because after almost 15 years, we now finally have an oral HMA. This is going to be really important in our field for patients with MDS and potentially other malignancies in the future.

The end point of the study was to see if the PK profiles were similar or not comparing IV decitabine to oral decitabine. What we found actually is that the PK ratio was between 98% to 99% concordant, so virtually identical in terms of their pharmacological characteristics. That was a very simple end point of this study, and that was really achieved at almost 100%.

TARGETED ONCOLOGY: How does this combination compare to other agents in the space?

Garcia-Manero: The idea here is not to develop a totally new class of compounds but to develop a new way to deliver therapy. That is basically the scaffold of what we do for patients with MDS and AML. The purpose of this study was to develop and demonstrate that this oral compound is virtually identical to IV decitabine. Again, why this is important is because the patients now will not have to come 5 days a month to a clinic and spend a couple of hours there when they can take this oral formulation at home. That's actually probably not the most important thing in my mind, as I think this oral compound now is opening the doors to multiple ways to treat our patients.

We could now develop very simple ways to treat patients with lower-risk MDS with perhaps lower doses or shorter risk carriers of this compound. The studies actually are ongoing right now. This community compound is also going to allow us to develop multiple oral combinations. This is the future. For instance, if you look at the way we treat high-risk MDS or AML, most likely it incorporates another drug that is also ordered, so there is a lot of interest with a compound known as venetoclax (Venclexta). We actually are now giving for IV decitabine for 10 days in patients with AML. Now, this is not the label of these compounds, and I'm not saying that this drug will be used today in that context, but the research that is going in this field switches that we could then perhaps use more intense programs for particular patients with high-risk disease. You’re going to see clinical trials for patients with AML using longer exposure to this compound, and this will be facilitated by this product formulation instead of having a patient come in multiple days during the month to clinic.

To summarize, the oral formulation is going to be a major advantage to our patients that now are going to be able to receive most of this therapy at home, not having to be seen every day in our clinic. That is the immediate effect for our patients, but what is going to happen is this oral formulation, with its flexibility, is going to allow for multiple ways to treat our patients both with MDS and AML. That is the most exciting thing for investigators in this field.

TARGETED ONCOLOGY: With this being administered orally, is there an option for patients to take this in the outpatient setting, and what kind of impact might that have for patients?

Garcia-Manero: Of course, they will be taking this at home, so this will be a total outpatient therapy. They will be getting this at home like they will do with any oral therapy, so this is going to be a major improvement in the quality of life of our patients for sure.

TARGETED ONCOLOGY: Could you discuss the safety profile observed with the combination?

Garcia-Manero: This is a very important question because of course, every time we give a drug orally that is some form of chemotherapy at the end, you think this is going to have major side effects in terms of nausea, vomiting, diarrhea, etc. However, we saw a toxicity profile very similar to what you will see with the IV decitabine. It is a very safe compound that we have used now for close to 2 decades in patients with MDS and AML, so that toxicity profile is also excellent with this compound.

TARGETED ONCOLOGY: Now that the combination has received FDA approval, how do you see it making an impact on the treatment landscape overall?

Garcia-Manero: Yeah, this is going to be very important. We are very excited about this, and it's going to start a new approach for our patients. We've been using these compounds for so many years that it's almost automatic how we write this prescription, so it's going to be another challenge because I think it's going to be very exciting and in a good way. I think the patients are going to demand this the moment they know that this drug finally is approved. They're going to ask, why are you giving me this IV when I can get it orally. I can tell you anecdotally that there is no week in my practice that the patient does not ask me when these oral compounds are going to be ready because they are tired of these injections and having to come multiple days a month. I think this is something that the providers are going to embrace.

TARGETED ONCOLOGY: What is your key takeaway from all this this study and the approval?

Garcia-Manero: The key message is that now we have finally, after 15 years of trying, an oral HMA that has an identical pharmacological and PK profile to that of the IV form with an excellent toxicity profile. We believe that this drug will replace IV decitabine in clinical practice, and we have a really major impact on future research for our patients with MDS and AML.

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