Azacitidine–Eprenetapopt Combo Yields Responses in Patients With TP53-Mutant MDS

Phase 1b/2 study findings suggest that therapy with eprenetapopt plus azacitidine is well-tolerated and leads to high rates of clinical response and molecular remission in patients with TP53-mutant myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia (AML; J Clin Oncol. 2021 Jan 15. Epub ahead of print).

“Approximately 20% of patients with TP53-mutant [MDS] achieve complete remission (CR) with hypomethylating agents,” wrote David A. Sallman, MD, Malignant Hematology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, and colleagues.

Using a cohort of 55 patients with TP53-mutant MDS or AML with 20% to 30% marrow blasts, Dr Sallman et al evaluated the safety, efficacy, and recommended phase 2 dose of eprenetapopt—a novel, first-in-class, small molecule that restores wild-type p53 functions in TP53-mutant cells—combined with azacytidine.

Of the study participants, 40 had MDS, 11 had AML, and 4 had MDS/myeloproliferative neoplasms with at least 1 TP53 mutation.

Findings demonstrated an overall response rate of 71%, with 44% achieving CR. Among the 40 patients with MDS, 29 (73%) had responses, including 20 (50%) achieving a CR and 23 (58%) achieving a cytogenetic response. Among those with AML, the overall response and CR rates were 64% (n = 7) and 36% (n = 4), respectively.

According to next-generation sequencing, patients with only TP53 mutations had higher rates of CR (69% vs 25%; P = .006). Furthermore, patients with responses had significant reductions in TP53 variant allele frequency and p53 expression as per immunohistochemistry, with 21 (38%) achieving complete molecular remission (variant allele frequency <5%).

The median overall survival (OS) was 10.8 months, with significant improvement in responding (14.6 months) versus nonresponding (7.5 months) patients by landmark analysis (P = .0005).

A total of 19 (35%) patients underwent allogeneic hematopoietic stem-cell transplantations, with a median OS of 14.7 months.

“Adverse events were similar to those reported for azacitidine or eprenetapopt monotherapy, with the most common grade ≥3 adverse events being febrile neutropenia (33%), leukopenia (29%), and neutropenia (29%),” Dr Sallman and co-investigators reported.

“Combination treatment with eprenetapopt and azacitidine is well-tolerated yielding high rates of clinical response and molecular remissions in patients with TP53-mutant MDS and oligoblastic AML,” they concluded.—Hina Porcelli