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 AML Hub is happy to provide a summary.

Study designs^1,3

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).

NCT03072043¹

Phase Ib/II open-label, multicenter, dose-escalation/-expansion study.
3 × 3 dose escalation and identification of dose-limiting toxicities were used to determine the recommended phase II dose.
Primary endpoint: CR as defined by 2006 International Working Group criteria.

Secondary endpoints: Overall response rate (ORR), duration of response (DoR), and overall survival (OS).

Results

The intention to treat (ITT) and response evaluable populations comprised 55 and 45 patients, respectively.
Patient characteristics are shown in Table 1.

Table 1. Baseline characteristics of patients enrolled in the NCT03072043 trial.¹

Characteristic Data are % unless otherwise stated	All patients (N = 55)	MDS (n = 40)	AML (n = 11)	MDS/MPN (n = 4)
Female	53	43	73	100
Median age, years (range)	66 (34–85)	66 (34–80)	68 (47–85)	57 (41–79)
Age category ≥ 65 years	58	58	64	50
ECOG PS at screening 0 1 2	31 62 7	38 55 8	18 73 9	0 100 0
Risk* Intermediate High Very high	7 25 67	10 20 70	0 27 73	0 75 25
TP53 status p53 IHC ≥ 10% Median TP53 VAF % Median TP53 mutations per patient, n (range)	76 21 1 (1–3)	83 20 1 (1–3)	55 15 2 (1–2)	75 44 2 (2)
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. *Defined by the revised International Prognostic Scoring System

Efficacy

In the ITT population, ORR and CR rates were 71% and 44%, respectively. The hematological responses by disease type in the ITT population are shown in Table 2.

Table 2. Responses to eprenetapopt in combination with azacitidine in the ITT population of the NCT03072043 trial.¹

Response, %	All patients (N = 55)	MDS (n = 40)	AML (n = 11)	MDS/MPN (n =4)
ORR [95% CI]	71 [57–82]	73 [56–85]	64 [31–89]	75
Best response by IWG CR PR mCR 1 HI mCR HI SD NE PD	44 0 15 7 5 7 18 4	50 0 18 3 3 6 18 4	36 0 0 18 9 9 27 0	0 0 25 25 25 25 0 0
CR [95% CI]	44 [30–58]	50 [34–66]	36 [11–69]	0
Complete cytogenetic response	33	38	27	–
TP53 status NGS-negative Serial IHC ≤ 5%	38 47	43 48	36 55	0 NA
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.

Safety

No dose-limiting toxicities were observed in any of the 12 patients involved in the dose-escalation stage.
Recommended phase II dose of eprenetapopt + azacitidine: 100 mg/kg/d lean body mass (LBM).
The most common Grade ≥ 3 treatment-emergent adverse events (TEAEs) are shown in Table 3.
- < 5% were believed to be related to eprenetapopt.

Table 3. Grade ≥ 3 TEAEs observed in ≥ 5% of patients and in the intention to treat group.¹

Grade ≥ 3 TEAEs (n = 55)	Patients, %
Febrile neutropenia	33
Leukopenia	29
Neutropenia	29
Thrombocytopenia	25
Lung infection	25
TEAEs, treatment emergent adverse events.

Biomarker analysis

Patients who harbored mutations in TP53 alone demonstrated superior CR rates compared with patients who had concomitant mutations.

NCT03588078³

Phase II open-label, multicenter study.
Primary endpoint: Response in the ITT and evaluable population groups determined by the International Working Group (IWG) 2006 and 2003 criteria for MDS and AML, respectively.
Secondary endpoints:
- Safety
- OS
- DoR
- AML progression rate
- Association between TP53 variant allele frequency (VAF) and response

Results

Patient characteristics are shown in Table 4.

Table 4. Baseline characteristics of patients enrolled in the NCT03588078 trial.³

Characteristic Data are % unless otherwise stated	All patients (N = 52)	MDS (n = 34)	AML (n = 18)
Female, n	25	19	6
Median age, years (range)	74 (44–87)	74 (46–87)	72 (44–83)
Risk* Intermediate High Very high	8 10 48	12 15 74	–
Median TP53 mutations per patient (range)	1 (1–3)	1 (1–3)	1 (1–2)
AML classification Unfavorable	35	–	100
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.

Efficacy

Patient OS rates at the median follow up (9.7 months) are shown in Table 5.
Patient responses to therapy by disease classification are shown in Table 6.

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 AML with > 30% blasts (n = 7) Low blast count AML	10.4 3.0 13.9
MDS	12.1
≥ 3 treatment cycles	13.7
Response to therapy Responders Non responders p value	15.6 3.8 < 0.0001

Table 6. Responses to eprenetapopt in combination with azacitidine in the ITT population of the NCT03588078 trial.³

Response	All patients (N = 52)	MDS (n = 34)	AML 20–30% blasts (n = 11)	AML > 30% blasts (n = 7)
ORR, % CR CRi PR mCR† SD with HI	–	62 47 * 0 6 9	– 27 18 * * *	14 0 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. *For MDS, ORR included CR, mCR, PR, and SD with HI. For AML, ORR included CR and CRi. †mCR was used for MDS.

Safety

The most commonly observed adverse events (AEs) were febrile neutropenia (37%) and neurologic events (40%). Grade > 3 AEs were observed in three patients (one acute confusion and two ataxia) and were reversible by drug discontinuation.
Incidence of neurologic AEs was associated with reduced glomerular filtration (p = 0.01) and increased age (p = 0.05).
One patient with renal failure experienced early treatment discontinuation due to an eprenetapopt-related neurologic AE.

TP53 status

Of the patients who responded to treatment, 73% and 30% achieved TP53 VAF levels lower than the 5% and 0.1% thresholds, respectively.
TP53 VAF decrease was significantly coupled with response (p < 0.0001), CR (p = 0.002), and DoR (p < 0.0001).
Patients who achieved TP53 VAF levels lower than the 5% threshold demonstrated significantly improved DoR (p = 0.001) and OS (p < 0.0001).
Patients who achieved TP53 VAF levels lower than the 0.1% threshold demonstrated significantly improved OS (p < 0.05).

Conclusions^1,3

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 endorse 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.

Additional resources

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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