In a phase Ib/II study reported in the Journal of Clinical Oncology, David A. Sallman, MD, and colleagues found that the combination of azacitidine and the first-in-class small-molecule agent eprenetapopt produced high response rates in patients with TP53-mutant myelodysplastic syndromes (MDS). Eprenetapopt selectively induces apoptosis in TP53-mutant cancer cells.

David A. Sallman, MD

Study Details

The phase Ib/II study aimed to determine the safety, recommended phase II dose, and efficacy of the combination.

Fifty-five higher-risk patients with TP53-mutant MDS or acute myeloid leukemia (AML) with 20% to 30% marrow blasts were enrolled in the U.S. multicenter study between May 2017 and February 2019. The population consisted of 40 patients with MDS, 11 with AML, and 4 with MDS/myeloproliferative neoplasms (MPN). No dose-limiting toxicities were observed during the eprenetapopt dose-escalation phase, when patients subsequently received the agent at a fixed dose of 4,500 mg/d (100 mg/kg/d lean body mass equivalent) via 6-hour infusion on days 1 to 4 of 28-day cycles. Azacitidine was given at the standard dose of 75 mg/m² for 7 days in each cycle.

Response Rates and Survival

Among all patients, response was observed in 39 (71%), with complete remission in 24 (44%). Response and complete remission rates were 73% and 50% among patients with MDS, 64% and 36% among those with AML, and 75% and 0% among those with MDS/MPN.

Higher rates of complete remission were observed among the 62% of patients with only TP53 mutations vs 32% with co-occurring somatic mutations (69% vs 25%, P = .006). Patients who responded had significant reductions in TP53 variant allele frequency and p53 expression by immunohistochemistry, with 38% achieving complete molecular remission (variant allele frequency < 5%).

At a median follow-up of 10.5 months, median overall survival was 10.8 months in the entire population, including 10.4 months in the MDS group and 10.8 months in the AML group. In a landmark analysis of responders and nonresponders at 4 months, median overall survival was 14.6 months for responders vs 7.5 months for nonresponders (hazard ratio = 0.23, P = .0005). Median overall survival was 12.8 months in patients with complete remission vs 14.7 months among responders without complete remission (P = .63). Among 19 patients who went on to undergo allogeneic hematopoietic stem cell transplantation, median overall survival was 14.7 months.  

Adverse Events

Common adverse events of any grade that occurred during the eprenetapopt infusion phase were dizziness (36%), peripheral sensory neuropathy (31%), ataxia (24%), and tremor (20%), with all resolving after the infusion phase. Among the 15 patients with recurrent neurologic events, the initial occurrence was reported in cycle 1, with 14 having recurrence of the same event in subsequent cycles. No recurrent neurologic events worsened to grade ≥ 3. Three patients had eprenetapopt dose reductions for nausea, with no dose reductions for neurologic events being required. The most common grade ≥ 3 adverse events were febrile neutropenia (33%), leukopenia (29%), and neutropenia (29%).

The investigators concluded, “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.”

Dr. Sallman, of the Malignant Hematology Program, H. Lee Moffitt Cancer and Research Institute, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by a MDS Foundation Young Investigator Grant, Early Career Award of the Dresner Foundation, Edward P. Evans MDS Clinical Research Consortium, and National Cancer Institute. For full disclosures of the study authors, visit ascopubs.org.