Oral Decitabine/Cedazuridine Is an Effective, At-Home Treatment Option for MDS and CMML

James K. McCloskey II, MD

The oral formulation of decitabine (Dacogen)/cedazuridine (Inqovi) provides a bioequivalent and potentially more convenient alternative to intravenous (IV) therapy, allowing patients with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) to maintain their quality of life (QOL) during treatment with an effective at-home regimen, according to James K. McCloskey II, MD.

“Our goal for patients is to help them live longer and better with their disease, and they’re going to do that better at home,” McCloskey stated in an interview with OncLive®. “[Although] it may not seem that way on paper sometimes to investigators because [this oral formulation] is just a biosimilar, [at-home treatment] a big accomplishment from the [perspective] of a patient.”

In the interview, McCloskey discussed long-term follow-up data from the phase 3 ASCERTAIN trial (NCT03306264), which showed that the toxicities observed with oral decitabine/cedazuridine were consistent with those associated with IV decitabine.1 Results published in The Lancet Hematology also showed that the primary end point of total exposure of oral decitabine/cedazuridine vs IV decitabine was 98.93% (90% CI, 92.66%-105.60%), which suggested equivalent pharmacokinetic exposure [between the compounds].

McCloskey also highlighted important safety considerations when considering the oral regimen and ongoing research aimed at integrating oral hypomethylating agents (HMAs) into novel combination strategies.

McCloskey serves as the interim chief of the Division of Leukemia at John Theurer Cancer Center, Hackensack Meridian Health, in New Jersey.

OncLive: What was the importance of evaluating the differences between oral and IV administration of decitabine with or without cedazuridine in MDS and CMML?

McCloskey:In CMML and MDS, HMAs—including decitabine and azacitidine [Vidaza]—have been the standard of care [SOC] since the early 2000s. They have shown—especially in higher-risk disease—improved survival, improved QOL to some extent, and a reduction in the risk of [disease] transformation to leukemia. We’ve tried for some time to improve those outcomes [with these agents] for patients with higher-risk disease, without success. [HMAs are] still the SOC [for patients with higher-risk disease] in the United States and Europe. Additionally, these drugs have been shown to offer benefit to patients with lower-risk disease who might be transfusion dependent.

In both scenarios, especially when we consider QOL, one of the limiting factors for [treatment] has been that both the initial formulations of azacitidine and decitabine being were parenteral, meaning that they needed to be injected or infused for multiple days a month. For patients who might be receiving these drugs for several months, that time accumulates. That can be a barrier to [treating] those patients, because they need to spend multiple days a month in our clinic to receive these agents.

What was the key objective of the ASCERTAIN trial?

The goal of ASCERTAIN was to demonstrate whether an oral formulation of decitabine plus cedazuridine was bioequivalent [to IV decitabine]. In this trial, patients with MDS or CMML were randomly assigned to start treatment with either oral decitabine plus cedazuridine or IV decitabine in cycle 1. In cycle 2, they received whichever drug they didn’t receive in cycle 1. In cycle 3, we moved forward only with the oral combination. During the first 2 cycles, we obtained a variety of pharmacokinetic and pharmacodynamic labs to show that the serum levels and exposure to decitabine were equivalent whether it was administered orally or IV.

What did the results from this study reveal about the pharmacokinetic equivalence and safety of these different decitabine formulations?

Results showed that the exposure to the drug [in both oral and IV formulations] was 98.93% the same. [The formulations achieved] bioequivalence with a significant P value, suggesting that, for most patients, IV decitabine can be substituted with oral decitabine [to obtain] similar clinical results. The long-term follow-up of this study and subgroup analyses that have been [previously] presented demonstrate that the clinical outcomes of the patients receiving long-term oral decitabine are the same or better than what we’ve seen historically [with IV decitabine], although this publication does not address this directly.

That finding is a game changer. For instance, one of my patients was on this study for over 2 and a half years. When we consider the amount of time that patient would have sat in a chair in my office receiving an IV drug that could be given orally, [these findings are] life-changing for that patient.

What are some of the limitations and safety considerations associated with long-term use of the oral regimen?

There are some limitations. You need to make sure your patients have good gastrointestinal [GI] absorption. Patients who’ve undergone gastric bypass surgery may not be ideal candidates [for the oral formulation], and during the first few cycles, patients may be transfusion dependent and have a lot of follow-up requirements. However, the long-term exposure to this drug saves patients a lot of time. Additionally, by being able to maintain patients on the drug more regularly, we may offer them a better long-term response.

We don’t use IV [decitabine] as a single agent in MDS much anymore. Many of our patients have been converted to the oral [formulation]. [The efficacy of the oral formulation of this combination for patients with MDS and CMML] also opens the door [for its potential use] in other diseases. The National Comprehensive Cancer Network [NCCN] guidelines have now recognized [oral decitabine] as a possible combination partner with venetoclax [Venclexta] for patients with higher-risk MDS or acute myeloid leukemia [AML]. [In a] disease like AML, once the patient’s in remission, they might be able to receive an oral regimen. That’s a game changer in a disease where we recognize that HMAs are not curative.

How is the role of oral HMAs evolving in the management of MDS and AML? What ongoing clinical trials are shaping their future use?

Without a doubt, [oral formulations are] a consideration we’re talking about more and more. I’m having this conversation with patients, people who are developing clinical trials, and other companies who are interested in exploring [this treatment approach in] both AML and MDS. I always say we should consider [clinical trials] for patients to be treated with oral regimens, or incorporate oral decitabine as an option for those patients.

Several clinical trials are ongoing. Publications on the combination of venetoclax and oral decitabine have been [previously] presented, and we are awaiting the full manuscripts of the safety data from [those studies]. Based on early data, the NCCN has already included [oral decitabine plus cedazuridine] as a [category 2A recommendation for MDS]. Additionally, the drug is being evaluated in several other studies in combination with novel investigational agents.

Lastly, there is an ongoing study to develop oral azacitidine [in combination with] cedazuridine, which prevents degradation of these drugs in the GI tract. We just finished the initial phase 2 portion of that study and are awaiting enrollment to start on the expansion cohort. This is the beginning of the story for the oral HMAs. We will hopefully have oral azacitidine approved in the future.

What lessons from recent challenges with drug development in high-risk MDS may inform future research?

This is an exciting time, and [the feasibility of oral decitabine use] is a big improvement for our patients. We still have a lot of work to do, but it has been [an exciting] several years in high-risk MDS management. We’ve seen several drugs come close to commercial success in phase 2 studies and go into phase 3 trials, where they failed to meet their primary end points.

These failures underscore the importance of continuing to enroll patients onto clinical trials. It’s important to remember that your academic oncology colleagues probably have studies for these patients. [Academic and community oncologists] can often work together successfully because we [want to] move the needle for these patients.

For example, we often had patients on this trial who saw us [at John Theurer Cancer Center] for those initial 2 cycles where they were [spending] hours in my clinic to get their labs drawn, but their later follow-ups could be done locally, and [they just needed to attend] research visits with me. Here at Hackensack Meridian Health, I remain dedicated to bridging that divide [between academic and community oncology], because I know community providers have relationships with their patients that are incredibly valuable.

Reference

Garcia-Manero G, McCloskey J, Griffiths EA, et al. Oral decitabine-cedazuridine versus intravenous decitabine for myelodysplastic syndromes and chronic myelomonocytic leukaemia (ASCERTAIN): a registrational, randomised, crossover, pharmacokinetics, phase 3 study. Lancet Haematol. 2024;11(1):e15-e26. doi:10.1016/S2352-3026(23)00338-1