Expert Discusses Novel Treatment Approach for TP53-Mutant MDS and AML

Raajit K. Rampal, MD, PhD

A phase 3 study, which will evaluate the combination of APR-246 (eprenetapopt) and azacitadine, completed enrollment in early June, at which time plans were announced to submit applications for regulatory approval in both the United States and Europe.

APR-246 is a small molecule designed to reactivate p53 protein in a variety of solid and hematologic malignancies, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

The study of APR-246 combined with azacitidine is a multicenter clinical trial of 154 patients who will be randomized 1:1:1 to receive the combination or azacitidine monotherapy. The trial is 90% powered to identify a difference in complete response rates of 50% in the APR-246 combination arm versus 25% in the control arm.

In an interview with Targeted Oncology, Raajit K. Rampal, MD, PhD, hematologic oncologist, Memorial Sloan Kettering Cancer Center, discussed the novel agent, APR-246, and its significance for use in the patients with MDS and AML.

TARGETED ONCOLOGY: Why is the TP53 mutation in MDS and AML difficult to treat?

Rampal: What we have known historically is that patients with p53 mutations with MDS,

particularly those who have a complex karyotype, have a low response to therapy and have worse outcomes even with autologous stem cell transplant, which is the only curative measures for patients with MDS. There are a plethora of data showing that these patients have worse outcome in general.

The mechanisms by which TP53 mutation have an impact on disease continue to be explored, but it is clear to us that cytotoxic chemotherapy alone is not sufficient enough to treat these patients. Therefore, new approaches are needed to treat TP53-mutant MDS.

TARGETED ONCOLOGY: How does APR-246 differ from other therapeutic approaches?

Rampal: The reported mechanism of APR-246 is to induce refolding of the P53 protein. In doing this, it can resume its normal function in the context of chemotherapy allows for apoptosis to occur. That differs from just being another cytotoxic chemotherapy.

TARGETED ONCOLOGY: What was the rationale for the phase 3 clinical trial of APR-246 plus azacitidine for the treatment of frontline TP53-mutant MDS?

Rampal: There are a couple of early-phase studies that looked at APR-246 with azacitidine in patients with MDS and oligoblastic AML. What those studies from North America and Europe have shown is that there is an encouraging overall response rate that appears superior to what has been seen historically with azacitidine monotherapy. This observation was inclusive of patients having bone marrow remissions and hematologic improvement.

What is also interesting in the data that was presented at ASH 2019 from Moffitt Cancer Center researchers demonstrated that in a proportion of patients there is a reduction in the allele burden of TP53-mutant clone in some cases, it went below the detection limits of the sequencing assay that used, which suggests that this combination therapy is targeting the TP53-mutant clone.

The other observation that was interesting was that the patients who responded had a longer survival who didn’t respond. This is all suggestive of the nontarget effect against this particular mutant clone.

There are single-arm studies with preliminary data that tell us something about the toxicity and the potential efficacy of the regimen. Data from the phase 3 are what we need in order to understand whether or not this combination is effective.

TARGETED ONCOLOGY: What are the key goals of this study?

Rampal: The goal is to compare the rate of complete remission and duration of the remission in patient specifically with TP53-mutant MDS. The patients are randomized a standard azacitidine versus the APR-246 plus azacytidine.