The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia

Abstract

Targeting critical epigenetic regulators reverses aberrant transcription in cancer, thereby restoring normal tissue function^1-3. The interaction of menin with lysine methyltransferase 2A (KMT2A), an epigenetic regulator, is a dependence in acute leukaemia caused by either rearrangement of KMT2A or mutation of the nucleophosmin 1 gene (NPM1)^4-6. KMT2A rearrangements occur in up to 10% of acute leukaemias and have an adverse prognosis, whereas NPM1 mutations occur in up to 30%, forming the most common genetic alteration in acute myeloid leukaemia^7,8. Here, we describe the results of the first-in-human phase 1 clinical trial investigating revumenib (SNDX-5613), a potent and selective oral inhibitor of the menin-KMT2A interaction, in patients with relapsed or refractory acute leukaemia (ClinicalTrials.gov, NCT04065399). We show that therapy with revumenib was associated with a low frequency of grade 3 or higher treatment-related adverse events and a 30% rate of complete remission or complete remission with partial haematologic recovery (CR/CRh) in the efficacy analysis population. Asymptomatic prolongation of the QT interval on electrocardiography was identified as the only dose-limiting toxicity. Remissions occurred in leukaemias refractory to multiple previous lines of therapy. We demonstrate clearance of residual disease using sensitive clinical assays and identify hallmarks of differentiation into normal haematopoietic cells, including differentiation syndrome. These data establish menin inhibition as a therapeutic strategy for susceptible acute leukaemia subtypes.

Fig. 1. Transcriptional changes following treatment with the menin inhibitor revumenib in patients with relapsed or refractory acute leukaemia with KMT2Ar or mutated NPM1.

RNA-seq before and after treatment with revumenib, showing downregulation of critical leukaemogenic target genes MEIS1, HOXA9 and PBX3 and increase in expression of genes associated with differentiation (CD11b, CD14), with transcriptional suppression of FLT3, a putative transcriptional target of MEIS1. The change in bone marrow blast percentage following treatment is shown. Box plots represent median gene expression or median bone marrow blast percentage, and the 95% CI along with percentage change in gene expression following treatment. Responders are shown in red, nonresponders in black. Results were obtained using a paired t-test with a two-sided P value. Adjustments were not made for multiple comparisons. This analysis included a cohort of 21 evaluable patients. Revumenib was administered in continious 28-day cycles. C2D1, day 1 of treatment cycle 2.

Fig. 2. Characterization of remissions with the menin inhibitor revumenib in susceptible relapsed or refractory acute leukaemia subtypes.

a, Time to response, duration of treatment (censored at time of HSCT) and patient status by the cutoff date. *Other reasons for treatment discontinuation included no response, relapse, death and donor lymphocyte infusion. b, Kaplan–Meier curve of duration of response (DOR) in patients with CR or CR/CRh without censoring at the time of an allogeneic stem cell transplant performed in 12 of 18 evaluable patients.

Extended Data Fig. 1. Revumenib suppresses both KMT2Ar and NPM1-mutant AML in preclinical models of leukaemia.

NSG mice were engrafted with the KMT2Ar cell line MOLM-13 (a; n = 10) or patient derived xenografts (PDX) harbouring either a KMT2Ar (d; n = 5) or NPM1 mutation (g; n = 5). Mice were treated for 28 days with revumenib, which was formulated in chow, across a dose range of 0.025% to 0.2% (a) or at 0.1% fixed dose (d, g). Leukaemic burden (CD45+) was assessed at end of treatment (b; 0.025%: n = 3; 0.05-0.2%: n = 5, data represent mean ± SEM) or throughout the study (d, g; data represent mean ± SEM). For MOLM-13 engrafted mice, revumenib showed clear dose-dependent exposure (c; n = 3 with 3 individual measurements per timepoint and dose, data represent mean ± SD), which translated into dose-responsive effect on survival benefit (a) and leukaemic burden at end of treatment (b). Similarly, revumenib treatment of the PDX models led to significant suppression of leukaemic burden and significant survival benefit in each (d, g). P-values were determined by log-rank (Mantel–Cox) tests. Adjustments were not made for multiple comparisons. Revumenib treatment also led to broad changes in the transcriptional program (f, i; n = 3 per treatment group; GEO accession number for RNAseq data, GSE216730) with GSEA results consistent with previously reported signatures (e, h; n = 3 per treatment group). GSEA, gene set enrichment analysis; NES, normalized enrichment score; NSG, NOD scid gamma; PDX, patient-derived xenograft; SD, standard deviation; SEM, standard error of the mean.

Extended Data Fig. 2. CONSORT diagram and patient disposition on trial.

The CONSORT diagram shows the number of patients from Arms A and B who discontinued treatment and lists the reasons for treatment and study discontinuation.

Extended Data Fig. 3. Dose escalation schema.

The revumenib dose was adjusted based on the body surface area (BSA) for patients weighing less than 40 kg as indicated for each corresponding dose level shown in parentheses. CYP3A4i, cytochrome P450 3A4 inhibitor; q12h, every 12 h; R/R, relapsed or refractory.

Extended Data Fig. 4. Morphologic evidence of myeloid differentiation.

Photomicrographs of bone marrow biopsies demonstrating morphologic evidence of myeloid differentiation in a patient who achieved complete remission; magnification is 40x.

Extended Data Fig. 5. Changes in peripheral blood during differentiation syndrome are associated with the menin inhibitor revumenib.

Example from a 71-year-old patient with KMT2Ar AML relapsed after an allogeneic stem cell transplant, who received revumenib at 339 mg PO q12h (Arm A), and achieved CRh, MRD negative remission. Differentiation syndrome manifested as chest pain with a small pericardial effusion, and a possible prodrome of neck pain likely related to expansion of cervical nodes, all resolved promptly with initiation of steroids followed by tapering doses. Hydroxyurea was used to control leukocytosis. AML, acute myeloid leukaemia; ANC, absolute neutrophil count; CRh, complete remission with partial haematologic recovery; MRD, minimal or measurable residual disease; PB, peripheral blood; PO, by mouth; q12h, every 12 h; WBC, white blood cell.

Extended Data Fig. 6. Dose proportional exposure was achieved across both arms.

The half-life of revumenib in Arm A (without strong CYP3A4 inhibitors) was approximately 3 h at the cycle 1 day 8 assessment of the 276-mg q12h dose level and was approximately 8 h at the same assessment in Arm B (with a strong CYP3A4 inhibitor) at the 163-mg q12h dose level. Data represent mean ± SD. Data cutoff date for pharmacokinetic analysis was July 11, 2022. CYP3A4, cytochrome P450 3A4; q12h, every 12 h; SD, standard deviation.

Extended Data Fig. 7. Response in extra-medullary disease.

A. PET scan at baseline and after 2 cycles of treatment. B. Computed tomographic scans of target lesions and spleen from a 19-year-old with relapsed KMT2Ar AML, previously treated with three prior lines of therapy including 2 allogeneic stem cell transplants and local radiation to the spleen and abdominal nodes, received revumenib at 276 mg PO q12h (Arm A), achieved CRh, MRD negative remission with resolution of extramedullary disease in abdominal nodes and spleen. AML, acute myeloid leukaemia; AP, anterior-posterior; CRh, complete remission with partial haematologic recovery; D, day; FDG, fluorodeoxyglucose; MRD, minimal or measurable residual disease; PET, positron emission tomography; PO, by mouth; q12h, every 12 h; SUV, standardized uptake value.

Extended Data Fig. 8. Overall survival in patients with KMT2Ar or mutated NPM1.

OS, overall survival.

Extended Data Fig. 9. Kaplan-Meier curve of duration of response in patients with complete remission or complete remission with partial haematologic recovery with censoring at time of the allogeneic stem cell transplant.

DOR, duration of response; NR, not reached.

Extended Data Fig. 10. Mutation analysis and response.

This cohort included 37 patients evaluable for this analysis. CR, complete remission; CRh, complete remission with partial haematologic recovery; CRp, complete remission with incomplete platelet recovery; MLFS, morphologic leukaemia-free state; NR, not reached; PD, progressive dVAF, variant allele frequency.