Eprenetapopt-based regimen shows promise for TP53-mutated myelodysplastic syndrome, AML
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Eprenetapopt plus azacitidine appeared well-tolerated and yielded high remission rates among patients with TP53-mutated myelodysplastic syndrome and oligoblastic acute myeloid leukemia, according to results of a phase 1b/phase 2 trial.
The study, published in Journal of Clinical Oncology, supports further evaluation of the addition of eprenetapopt (APR-246, Aprea Therapeutics), a first-in-class mutant p53 reactivator, to azacitidine among this population of patients, according to the researchers.
“The data a promising and support the current phase 3, multicenter trial, which we hope will lead to FDA approval and a new much-needed treatment option for this patient population,” David A. Sallman, MD, assistant member of the malignant hematology department at Moffitt Cancer Center, said in a press release.
Hypomethylating agents like azacitidine and decitabine confer complete remissions among approximately 20% of patients with TP53-mutated myelodysplastic syndrome; however, these remissions are brief, with median OS ranging from 5 to 12 months, according to study background.
“Patients with TP53-mutant disease, which is roughly 10% to 20% of AML and de novo myelodysplastic syndrome cases, don’t have many options for therapy, with nondurable responses to standard therapy,” Sallman said. “There is clearly a need for new, targeted therapies for this patient population.”
Sallman and colleagues evaluated whether the addition of eprenetapopt to azacitidine would improve outcomes for this group, and they sought to determine the safety and recommended dose of the combination.
The analysis included 55 patients (median age, 66 years; 53% women) with at least one TP53 mutation who had not previously received a hypomethylating agent. Of them, 40 had myelodysplastic syndrome, 11 had AML with 20% to 30% marrow blasts, and four had myelodysplastic syndrome/myeloproliferative neoplasm overlap syndrome.
In the dose-escalation phase of the trial, 12 patients received eprenetapopt monotherapy at three dose levels prior to the start of combination therapy — 50 mg/kg, 75 mg/kg or 100 mg/kg lean body mass equivalent. Because no dose-limiting toxicities occurred, researchers selected 100 mg/kg lean body mass equivalent (4,500 mg daily per patient) as the recommended phase 2 dose, given as IV infusions on days 1 through 4 of each 28-day cycle along with standard-dose azacitidine for 7 consecutive days.
Complete remission, as defined by 2006 International Working Group criteria, served as the study’s primary endpoint. Secondary endpoints included overall response rate, duration of response and OS.
Median follow-up was 10.5 months.
Researchers reported an ORR of 71%, with 44% of patients achieving complete remission.
Among patients with myelodysplastic syndrome, the ORR was 73%, with 50% achieving complete remission and 58% achieving cytogenetic response.
Among patients with AML, the ORR was 64% and complete remission rate was 36%.
Median OS in the intent-to-treat population was 10.8 months (95% CI, 8.1-13.4), with landmark analyses showing longer median OS among responders vs. nonresponders (14.6 months vs. 7.5 months; P = .0005). Among 19 patients (35%) who underwent allogeneic hematopoietic stem cell transplant, median OS was 14.7 months (95% CI, 8.6-20.9).
Researchers noted that patients with isolated TP53 mutations had a higher rate of complete remission than those with co-occurring mutations (69% vs. 25%; P = .006).
Additionally, trial results showed patients had significant reductions in TP53 variant allele frequency and p53 expression by immunohistochemistry, with 21 (38%) achieving complete molecular remission using a variant allele fraction cutoff of 5%.
Adverse events appeared similar to those reported for azacitidine or eprenetapopt monotherapy. The most common grade 3 or worse adverse events included febrile neutropenia (33%), leukopenia (29%) and neutropenia (29%).
The 44% complete remission rate observed in this study “is substantially higher than previously reported” with single-agent hypomethylating agents, the researchers wrote, adding that the response rate appeared consistent with results of a phase 2 study of eprenetapopt and azacitidine conducted by Groupe Francophone des Myélodysplasies.
“Together,” Sallman and colleagues wrote, “these data support the ongoing pivotal phase 3, multicenter, randomized study of eprenetapopt in combination with azacitidine vs. azacitidine alone in patients with TP53-mutant myelodysplastic syndromes.”
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