TP53 Modifier Impresses in Early MDS/AML Study

A drug that targets a common mutation in myelodysplastic syndromes (MDS) led to historically high response rates as initial treatment for MDS and acute myeloid leukemia (AML), a small clinical trial showed.

Overall, 71% of patients with TP53-mutant conditions responded to the combination of eprenetapopt and azacitidine, including complete remissions (CRs) in 44%. A majority of patients with MDS or AML had objective responses. Patients who responded to eprenetapopt lived almost twice as long as those who did not benefit from the treatment.

The results compared favorably to standard-of-care treatment with hypomethylating agents, which typically achieve CRs in about a fifth of patients, David A. Sallman, MD, of Moffitt Cancer Center in Tampa, Florida, and coauthors reported in the Journal of Clinical Oncology.

“The way the drug works is it kind of binds the misfolded [TP53] protein, and then sort of restores its function to kill the cancer cell,” Sallman told MedPage Today. “You can actually look at this based on standard immunohistochemistry [IHC]. You see a lot of positivity but not all patients have it, despite having somewhat similar mutations. So that was a very strong predictor of complete remissions in our study, as well as the absence of other mutations. That speaks to the biological rationale of the drug, and I think those questions will be quite critical to evaluate in the [ongoing] phase III study.”

TP53 mutations occur in as many as 20% of de novo MDS and AML, increasing to 30-40% of patients with treatment-related disease. Standard treatment with hypomethylating agents, such as azacitidine and decitabine, produces CRs in approximately 15-20% of patients with TP53-mutant or wild-type MDS, the authors noted. However, remissions tend to be short lived, associated with median overall survival (OS) of 5 to 12 months. Higher mutation burden is associated with even worse prognosis (median OS 6-8 months).

Eprenetapopt is a first-in-class molecule that selectively induces apoptosis in TP53-mutant cancer cells to restore normal function. Laboratory studies demonstrated cytotoxic synergism when eprenetapopt was combined with azacitidine. A phase I study showed that eprenetapopt had single-agent clinical activity in association with activation of p53-dependent pathways in hematologic malignancies.

Sallman and coauthors reported findings from a phase I/II study to evaluate eprenetapopt in combination with azacitidine in untreated MDS (n=40), AML (n=11), and MDS/myeloproliferative neoplasms (MDS/MPNs, n=4). All the patients had at least one TP53 mutation, and about 40% had TP53 variants and other somatic mutations. A majority of the patients were 65 or older, more than 90% had high- or very high-risk disease, and 69% were transfusion dependent.

Patients received intravenous infusions on days 1-4 of 28-day cycles and azacitidine by subcutaneous injection on 7 consecutive days or by 2 + 5 administration. The primary endpoint was CR, and key secondary endpoints included overall response rate (ORR), duration of response (DOR), and OS.

The most common adverse events (AEs) were gastrointestinal in nature, including nausea (64%), vomiting (45%), constipation (42%), and diarrhea (33%). Grade ≥3 AEs included febrile neutropenia (33%), leukopenia and neutropenia (29% each), and lung infection and thrombocytopenia (25% each). No other grade ≥3 AEs occurred in more than two patients.

An intention-to-treat (ITT) efficacy analysis showed CR rates of 50% and 36% for the MDS and AML subgroups, respectively, and ORRs of 73% and 64%. The median time to response was 2.1 months and to CR was 3.1 months.

A response-evaluable subgroup of 45 patients had an ORR of 87% (the same for MDS and AML) and CR rates of 53% overall — 61% in the MDS subgroup and 50% in the AML group. Additionally, 59% of patients had cytogenetic responses (41% complete responses).

After a median follow-up of 10.5 months, the ITT population had a median OS of 10.8 months, including 10.4 months for the MDS cohort and 10.8 months for the AML cohort. Responding patients had a median OS of 14.6 months versus 7.5 months for patients who did not respond to the treatment (P=0.0005). In about a third of cases, systemic treatment served as a bridge to stem-cell transplant. Those patients had a median OS of 14.7 months, and transplantation did not significantly affect the survival hazard, the authors reported.

A biomarker analysis showed that patients who had only TP53 mutations had a CR rate of 69%, as compared with 25% for patients who also had other mutations (P=0.006). Accumulation of p53 protein ≥10 by IHC also was associated with a higher CR rate (66% vs 13%, P=0.01). Clearance of TP53 variant allele frequency by next-generation sequencing had a significant association with CR (P<0.0001).

Most patients treated thus far with eprenetapopt had no prior treatment or at least no prior exposure to a hypomethylating agent, said Sallman. The drug’s performance in the relapsed/refractory setting will be a focus of future studies.

“Testing and readout for refractory is a really critical question because that’s a group of patients who really have nothing [with respect to treatment options],” he said.