Phase 3 Data With Eprenetapopt Plus Azacitidine Anticipated in High-Risk MDS/AML

David Sallman, MD, discusses the combination of eprenetapopt and azacitidine, a new standard of care for patients with myelodysplastic syndromes with a susceptible TP53 mutation.

The combination of eprenetapopt (APR-246) and azacitidine couple represent a new standard of care for patients with myelodysplastic syndromes (MDS) with a susceptible TP53 mutation, according to David Sallman, MD, and now, a phase 3 trial with the combination has completed enrollment.

Results from a phase 2 trial presented during the 2020 European Hematology Association Congress showed promising response rates with the eprenetapopt plus azacitidine in a very high-risk population of patients with TP53-mutated MDS and acute myeloid leukemia (AML).

The regimen resulted in a 76% response rate, which included a 53% complete response (CR)/CRi and a 11% marrow CR. Additionally, 3% of patients had a partial response with the treatment and 11% achieved stable disease and hematological improvement (SD+HI). In a subset of patients with MDS (n = 28), the response rate was 75%, with more than half, or 57%, of patients achieving a CR. In the intent-to-treat population, the response seen with the combination was 56%, which included a 38% CR/CRi, an 8% marrow CI, a 2% PR, and a 8% SD+HI. At a median follow-up of 8.5 months, the median overall survival (OS) had not yet been reached.

Earlier this year, in January 2020, the FDA granted a breakthrough therapy designation to the combination for the treatment of patients with MDS and a susceptible TP53 mutation. Now, investigators are examining the combination in a phase 3 trial, which recently completed enrollment.

“This is the first phase 3 study ever to focus specifically on a TP53-mutant population for high-risk MDS,” said Sallman. “As such, if the study is positive, eprenetapopt could become the new standard treatment for this patient population, the majority of whom are higher risk and have a poor prognosis.”

In an interview with OncLive, Sallman, an assistant member in the Department of Malignant Hematology at Moffitt Cancer Center, discussed the combination of eprenetapopt and azacitidine as a treatment for high-risk patients with TP53-mutant MDS and AML.

OncLive: Could you discuss the historical challenges of targeting TP53 mutations?

Sallman: TP53 is a molecular subset of patients with myelodysplastic syndrome [who have] really done poorly on standard-of-care therapies. The median OS in patients is somewhere between 6 and 12 months, really 7-8 months; that is including treatment with standard therapies, such as azacitidine. Even with allogeneic stem cell transplantation, which is really the only curative treatment, this group of patients tends to do significantly inferior. However, it still raises the question of whether this therapy should be offered as a standard treatment to these patients, given their poor outcomes.

Historically, many novel agents have been investigated in MDS but, until recently, none of the data have been exciting with regard to TP53-mutant disease. In terms of targeting TP53 mutations, this is a novel class of drugs, known as the p53 reactivators, which focus on restoring the function of p53. Although [these inhibitors] do not directly eliminate the mutation, they restore function of [p53] so that they can kill the cancer cells from within.

Could you elaborate on the mechanism of eprenetapopt and prior data with this agent?

Eprenetapopt is actually a prodrug. Under physiological pH, it’s converted to MQ, which forms specific covalent bonds with residues in the TP53 protein; this allows for a thermodynamic shift to a wild-type conformation and then p53 can induce normal activities, such as cell cycle arrest and apoptosis. Results from a phase 2 trial analyzing eprenetapopt were previously presented at the 2019 ASH Annual Meeting, where the vast majority of patients responded [to the agent. We saw] CR rates of over 50%, near 60% in the MDS cohort, with favorable outcomes observed across the board. Earlier presentations of these data and the high CR rates reported in a molecular cohort that has no great treatment options available led to the development of the ongoing, randomized phase 3 study. The trial is examining eprenetapopt plus azacitidine versus azacitidine alone and has a primary end point of improving CRs.

The trial has completed enrollment and data are anticipated later this year. What is the expectation for the trial?

We’re excited about the data from our presentation, along with results from a nearly identical trial that had been presented by Thomas Cluzeau, MD, PhD, of the Central University Hospital of Nice. We collaborated on these projects from the start and they have [yielded] quite comparable [results] in terms of both safety and response.

The cohorts validate each other nicely. Complete remission rates are significantly increased to over 50%, particularly in the cohort with MDS. The combination has been well tolerated. A low number of early death issues [have been reported] and adverse effects (AEs) include typical neurological toxicities, which occur during infusion. Although, these events were self-limited, resolved in all cases, and they typically could be managed or prevented with medications like prochlorperazine (Compazine).

We're excited that this phase 3 trial will confirm that this agent truly does improve CR rates in this molecular subset.

What are some of the next steps for this agent?

Although the median OS appears to be improved with eprenetapopt over the standard of care, further improvements can be made. Thinking about novel triplet regimens down the road might be quite important for this patient population. We also need to analyze how these patients do with transplants and determine how we can better improve outcomes.

Is there anything else that you wanted to add about this research?

The trial is reflective of patients with very high-risk MDS, so there has been some discussion based on data presented during the ASH Annual Meeting, where biallelic TP53 is a strong predictor of inferior overall outcomes.

If we look at our data, 90% of the cohort consists of very high-risk patients who have multiple p53 mutations or mutations in the setting of the complex carrier type, frequently with alterations of chromosome 17. The population is very reflective of this high-risk group. The question of whether we can improve response rates in lower-risk patients [is still open], but this is a rare subset of patients. I’m hopeful that as these data read out in the not-too-distant future, we can have a new standard of care for this high-risk patient group.


Cluzeau T, Serbert M, Rahme R, et al. APR-246 with azacitidine in TP53 mutated myelodysplastic syndromes and acute myeloid leukemia: a phase 2 study by Francophone Des Myelodysplasies. Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual. Abstract S181.