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Patients with TP53-mutant myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) experience suboptimal responses to currently available treatments. Although remission rates with hypomethylating agents are comparable between patients with TP53-mutant and wildtype MDS, TP53 mutations are associated with significantly reduced complete remission (CR) duration.1
Herein lies an unmet clinical requirement for targeted therapies in the TP53-mutant MDS/AML setting. The small molecule TP53 activator, eprenetapopt (APR-246), has exhibited synergy with azacitidine both in vitro and in vivo,2 and is currently being evaluated in several clinical trials for the treatment of patients with AML/MDS and mutated TP53. Promising early clinical data resulted in the Fast Track designation of eprenetapopt by the U.S. Food and Drug Administration (FDA) for the treatment of TP53-mutant AML.
In July of 2020, a decision was made to expand a phase I trial (NCT04214860) to include an additional cohort of patients with TP53 mutations who will be treated with eprenetapopt plus azacitidine as a frontline treatment. This decision came following promising results from two independent phase Ib/II clinical trials, NCT030720431 and NCT03588078,3 and updated results from these studies have recently been published by David A. Sallman et al. and Thomas Cluzeau et al., respectively. The MDS Hub is happy to provide a summary.
The two studies followed a similar study design; evaluating the safety and efficacy of eprenetapopt in combination with azacitidine in patients aged ≥ 18 years with TP53-mutant MDS or AML. Patients had an Eastern Cooperative Oncology Group performance status of 0–2, were classified as having intermediate-, high-, or very high-risk disease, and had ≥ one TP53 mutation as determined by next-generation sequencing.
The key distinguishing features are that NCT03072043 enrolled patients with AML and 20–30% blasts, while the NCT03588078 trial included patients with AML with > 30% blasts, as well as allowing continued maintenance with eprenetapopt + azacitidine for up to 1 year following allogeneic stem cell transplant (allo-SCT).
Table 1. Baseline characteristics of patients enrolled in the NCT03072043 trial.1
Characteristic |
All patients |
MDS |
AML |
MDS/MPN |
---|---|---|---|---|
Female |
53 |
43 |
73 |
100 |
Median age, years (range) |
66 (34–85) |
66 (34–80) |
68 (47–85) |
57 (41–79) |
Age category |
|
|
|
|
ECOG PS at screening |
|
|
|
|
Risk* |
|
|
|
|
TP53 status |
|
|
|
|
AML, acute myeloid leukemia; ECOG PS, Eastern Cooperative Oncology Group performance status; IHC, immunohistochemistry; MDS, myelodysplastic syndromes; MDS/MPN, myelodysplastic syndromes/myeloproliferative neoplasms; VAF, variant allele frequency. |
Table 2. Responses to eprenetapopt in combination with azacitidine in the ITT population of the NCT03072043 trial.1
Response, % |
All patients |
MDS |
AML |
MDS/MPN |
---|---|---|---|---|
ORR [95% CI] |
71 [57–82] |
73 [56–85] |
64 [31–89] |
75 |
Best response by IWG |
|
|
|
|
CR [95% CI] |
44 [30–58] |
50 [34–66] |
36 [11–69] |
0 |
Complete cytogenetic response |
33 |
38 |
27 |
– |
TP53 status |
|
|
|
|
AML, acute myeloid leukemia; CI, confidence interval; CR, complete remission; HI, hematologic improvement; IHC, immunohistochemistry; IWG, International Working Group; mCR, marrow complete remission; MDS, myelodysplastic syndromes; MDS/MPN, myelodysplastic syndromes/myeloproliferative neoplasms; NA, not applicable; NE, not evaluable; NGS, next-generation sequencing; ORR, overall response rate; PD, progressive disease; PR, partial remission; SD, stable disease. |
Table 3. Grade ≥ 3 TEAEs observed in ≥ 5% of patients and in the intention to treat group.1
Grade ≥ 3 TEAEs |
Patients, % |
---|---|
Febrile neutropenia |
33 |
Leukopenia |
29 |
Neutropenia |
29 |
Thrombocytopenia |
25 |
Lung infection |
25 |
TEAEs, treatment emergent adverse events. |
Patients who harbored mutations in TP53 alone demonstrated superior CR rates compared with patients who had concomitant mutations.
Table 4. Baseline characteristics of patients enrolled in the NCT03588078 trial.3
Characteristic |
All patients |
MDS |
AML |
---|---|---|---|
Female, n |
25 |
19 |
6 |
Median age, years (range) |
74 (44–87) |
74 (46–87) |
72 (44–83) |
Risk* |
|
|
– |
Median TP53 mutations per patient (range) |
1 (1–3) |
1 (1–3) |
1 (1–2) |
AML classification |
|
– |
|
AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; M/F, male/female; MLD, multilineage dysplasia; ULD, unilineage dysplasia; VAF, variant allele frequency. *Defined by the revised International Prognostic Scoring System. |
Table 5. OS in the ITT population of the NCT03588078 trial who received eprenetapopt in combination with azacitidine.3
Patient population, (N = 52) |
Median OS, months |
---|---|
ITT |
12.1 |
AML |
10.4 |
MDS |
12.1 |
≥ 3 treatment cycles |
13.7 |
Response to therapy |
|
Table 6. Responses to eprenetapopt in combination with azacitidine in the ITT population of the NCT03588078 trial.3
Response |
All patients |
MDS |
AML 20–30% blasts |
AML > 30% blasts |
---|---|---|---|---|
ORR, % |
– |
62 |
– |
14 |
Median DoR, months |
11.3 |
10.4 |
14.0 |
11.5 |
Median DoCR, months |
11.7 |
11.4 |
14.0 |
NE |
AML, acute myeloid leukemia; CR, complete remission; CRi, CR with incomplete count recovery; DoCR, duration of CR; DoR, duration of response; mCR, marrow CR; MDS, myelodysplastic syndromes; NE, not evaluable; ORR, overall response rate; SD with HI, stable disease with hematologic improvement. |
Both clinical trials report the feasibility of combining eprenetapopt with azacitidine for the treatment of patients with TP53-mutant MDS or AML, a high-risk patient population with limited treatment options. Eprenetapopt plus azacitidine demonstrated an encouraging safety profile and promising remission rates. Results from these studies endorsed the phase III trial (NCT03745716) comparing eprenetapopt plus azacitidine versus azacitidine alone for the treatment of patients with TP53-mutant MDS. Unfortunately, this trial did not meet its primary endpoint in improving CR rates in the latest interim analysis.
Read a summary of the results from the GFM-APR trial (NCT03931291), investigating the safety and efficacy of eprenetapopt plus azacitidine as maintenance therapy for patients with TP53 mutant AML or MDS following allo-SCT, here.
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