Eprenetapopt/Azacitidine Shows Promise, Advances to Phase 3 Trial in TP53-Mutant MDS/AML

TP53 mutations have historically been difficult to target, said Naveen Pemmaraju, MD. However, preliminary data with the investigational small molecule eprenetapopt (APR-246) have shown promising activity in patients with TP53-mutant myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

On January 30, 2020, the FDA granted a breakthrough therapy designation to the combination of the eprenetapopt and azacitidine for the treatment of patients with MDS with a susceptible TP53 mutation. Prior to the 2020 designation, APR-246 received both orphan drug and fast-track designations from the FDA in MDS.

The breakthrough therapy designation is based on findings from a small phase 1b clinical trial, in which the combination of eprenetapoptand azacitidine led to a 100% objective response rate (ORR) among 5 patients with hypomethylating agent (HMA)–naïve, TP53-mutant MDS and oligoblastic AML. Moreover, 4 patients achieved a complete response (CR) with complete cytogenetic response and 1 patient achieved a bone marrow CR with partial cytogenetic response.¹ All patients who obtained CRs had high TP53 positivity at baseline according to immunohistochemistry.

No serious treatment-related adverse effects or dose-limited toxicities were noted with the combination, though grade 4 neutropenia and thrombocytopenia were reported.

At the 2020 European Hematology Association Congress, data from a phase 2 trial led by the Groupe Francophone des Myelodysplasies also showed high response rates with the combination in previously untreated patients with TP53-mutant MDS and AML. In response-evaluable patients, the ORR was 77%, including a 49% CR rate. In the subset of patients with MDS, the ORR was 75%, including a 57% CR rate. The response rate in intention-to-treat population (including patients with at least 30% blast AML) was 58%, including a 38% CR/CR with incomplete hematologic recovery (CRi) rate.²

A phase 3 clinical trial (NCT03745716), which is evaluating the combination for the frontline treatment of this patient population, completed accrual in June 2020. Results from the trial are expected in the second half of 2020.

“TP53 is extremely important as it is mutated in up to 50% of all human cancers,” said Pemmaraju. “That makes it one of the most common mutations in both solid and liquid tumors. We are seeing responses with this combination in this population that is considered high risk.”

In an interview with OncLive, Pemmaraju, an associate professor in the Department of Leukemia of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed what the early data with eprenetapoptin combination with azacitidine could mean for the future in MDS and AML.

OncLive: What makes TP53 a challenging target in MDS? What are your thoughts on the combination of eprenetapopt and azacitidine?

Pemmaraju: In 2020, one of the key concepts in MDS and AML has become targeting the TP53 axis in cancer cells. In addition to being ubiquitous, TP53 has historically been extremely difficult—if not impossible—to directly target. Other molecules have tried to indirectly target the TP53 axis. Furthermore, across hematologic malignancies, most patients who are TP53-mutated invariably have a poor prognosis. This is across chronic and acute diseases.

TP53 is a well sought-after target [that highlights] an urgent unmet medical need [as it is a] poor prognostic feature.

Currently, there are several molecules [that are being tested] as single agents or in combination that are [showing real promise] in targeting TP53 mutations. One of those agents is eprenetapopt.

What data have we seen with this agent?

Eprenetapopt, as a single agent or in combination with the hypomethylating agent azacitidine, is showing early, but promising clinical data in patients with TP53-mutant MDS and potentially AML.

Of course, as with any novel combination of new drugs or old drugs, we have to [be observant] of toxicity. We also need to see what is happening to the TP53 variant allele burden and mutation pattern over time. It will also be of paramount importance to see what the long-term remission duration and overall survival of this novel combination is.

Certainly, targeting TP53 has been the holy grail of cancer, particularly in [hematologic] cancers. It is encouraging to see eprenetapopt, as well as other molecules like anti-CD47 molecules, that have some hint of activity in targeting TP53.

References

1. Sallman DA, DeZern A, Sweet K, et al. Phase Ib/II combination study of APR-246 and azacitidine (AZA) in patients with TP53 mutant myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Clin Can Res. 2018;78(suppl 13):CT068. doi:10.1158/1538-7445.AM2018-CT068
2. Cluzeau T, Sebert M, Rahme R, et al. APR-246 combined with azacitidine in TP53 mutated myelodysplastic syndromes (MDS) and acute myeloid leukemia. A phase 2 study by the groupe francophone des myelodysplasies (GFM). Presented at: 2020 European Hematology Association Virtual Congress; June 11-21, 2020; Virtual. Abstract S181.