First-in human-trial of revumenib in patients with KMT2A-rearranged or NPM1-mutated leukemia

Introduction

Lysine methyltransferase 2A rearrangements (KMT2Ar) and nucleophosmin 1 gene (NPM1) mutations arise in 80% of pediatric patients with acute lymphoblastic leukemia and ~30% of adult patients with acute myeloid leukemia. Revumenib, a potent selective oral inhibitor of the menin–KMT2A interaction, prevents the assembly of oncogenic KMT2A wild-type or fusion complexes on chromatin and has demonstrated significant anti-leukemic activity in preclinical KMT2Ar or NPM1-mutated leukemia models.

Currently, there are no targeted therapies specifically approved for acute leukemia with KTM2A or NPM1 mutations. Below, we summarize an article by Issa et al.¹ published in Nature on a first-in-human trial investigating the efficacy and safety of revumenib in patients with KMT2A-rearranged or NPM1-mutated relapsed/refractory (R/R) acute leukemia.

Study design

This is a phase I, multicenter, open-label dose-escalation study conducted across nine sites in the United States. Included patients were

• aged 1–79;
• had received a median of four previous lines of therapy; and
• had R/R acute leukemia with KTM2A rearrangements or mutated NPM1.

The study consisted of two parallel dose escalation cohorts of patients, with revumenib administered orally every 12 hours in continuous 28-day cycles (Figure 1). Primary endpoints included safety, maximum tolerated dose, recommended phase II dose, and characterization of the pharmacokinetic parameters of revumenib based on CYP3Ai. Exploratory endpoints included assessment of anti-leukemic activity in patients treated with KMT2Ar or mutated NPM.

CYP3A4i, cytochrome P450 3A4 inhibitor; KMT2A, Lysine methyltransferase 2A; KMT2Ar, KMT2A rearranged; NPM1, nucleophosmin 1; q12h, every 12 hours; R/R, relapsed/refractory.
*Adapted from Issa, et al.¹

Results

At the data cutoff (March 31, 2022), a total of 68 patients were treated, 82% of whom had R/R acute myeloid leukemia, 16% had acute lymphoblastic leukemia, and 2% had mixed-phenotype acute leukemia. Additionally, 46% had KMT2Ar, 21% had mutated NPM1, and 12% had neither mutation. Baseline characteristics are summarized in Table 1.

Table 1. Baseline characteristics*

ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; FLT3, FMS-like tyrosine kinase 3; HSCT, hematopoietic stem cell therapy; KMT2A, histone-lysine N-methyltransferase 2A; MPAL, mixed-phenotype acute leukemia; NPM1, nucleophosmin 1; RAS, renin-angiotensin-system; TP53, tumor protein 53. *Adapted from Issa, et al.1
Characteristic, % (unless otherwise stated)	Whole cohort (N = 68)
Median age, years	42.5
Male	38
Female	62
Median bone marrow blasts	59.5
Acute leukemia type
AML	82
Therapy-related AML	10
ALL	16
MPAL	2
Genotype
KMT2Ar	68
t(9;11)(p21;q23)	15
t(4;11)(q21;p23)	9
t(11;19)(q23;p13.1)	7
t(11;19)(q23;p13.3)	6
t(6;11)(q27;q23)	4
t(11;17)(q23;q12)	3
Other 11q23 translocations	24
Mutated NPM1	21
KMT2Ar and NPM1 wild type	12
Co-occurring mutations
FLT3	25
RAS	29
TP53	10
Previous therapies
Median number of prior therapies (range), n	4 (1–12)
Venetoclax	60
Allogeneic HSCT	46

Safety

Among the treated cohort, 67 patients (99%) experienced any-grade treatment-emergent adverse events (TEAE), and 53 (78%) had any-grade treatment-related adverse event (TRAE).

The most common any-grade TEAEs were prolongation of the QT interval, nausea, vomiting and febrile neutropenia; the incidence of the most common TEAE’s occurring in ≥20% of patients are reported in Figure 2.

ALT, alanine transaminase; ECG, electrocardiogram; TEAE, treatment-emergent adverse event.
*Adapted from Issa, et al.¹

• The most common Grade 3 treatment-related adverse event was the prolongation of the QT interval, occurring in nine patients; all were able to continue treatment at the next lower dose level.
• No treatment-related adverse events led to death or discontinuation of revumenib.
• Grade 2 differentiation syndrome was reported in 11 patients and all cases were resolved following corticosteroid treatment.

Pharmacokinetics and efficacy

• Doses of 226 mg and 276 mg every 12 hours in Arm A met the safety, tolerability, and pharmacokinetic prespecified criteria for the recommended phase II dose.
• Doses of 113 mg and 163 mg every 12 hours met the same prespecified criteria in Arm B.
• The overall response rate in efficacy-evaluable patients was 53% (n = 60).
• The rate of complete remission or complete remission with partial hematologic recovery was 30%, 78% of whom achieved undetectable minimal residual disease.

Conclusion

This study highlights that menin inhibition with revumenib monotherapy has encouraging anti-leukemic activity and safety in both children and adults with relapsed/refractory KMT2Ar or NPM1 mutated leukemia. Revumenib induced complete remissions and was associated with low Grade 3 or higher treatment-emergent adverse events.