Revumenib for patients with relapsed or refractory (R/R) Nucleophosmin 1–Mutated (NPM1m) Acute Myeloid Leukemia (AML): Outcomes by prior treatment in the phase 2 AUGMENT-101 study

Abstract BACKGROUND NPM1m AML accounts for ~30% of newly diagnosed adult AML and 12% of R/R AML cases. Approximately 50% of adult patients with NPM1m AML experience progressive disease or death after frontline treatment. Historical data suggest that only 48% and 10% of patients achieve complete remission (CR) after first salvage with high- or low-intensity treatments, respectively; CR rates decrease with each subsequent line (CR with second salvage, 30% and 8%; CR with subsequent salvage, 11% and 2%). Current standard of care varies depending on patient and disease characteristics and may include intensive chemotherapy, venetoclax (ven) ± hypomethylating agents, targeted therapies (such as FLT3 inhibitors [i], IDH1i, or IDH2i if a corresponding co-mutation is present), and allogeneic hematopoietic stem cell transplant (HSCT). Despite these available options, the prognosis for patients with R/R NPM1m AML remains poor, with a 1-year survival rate of only 16%. Novel treatments are needed. The menin–lysine methyltransferase 2A (KMT2A) interaction is a critical driver of leukemogenesis in NPM1m AML. Revumenib is a first-in-class, oral, selective inhibitor of the menin-KMT2A interaction. Safety (safety population, N=84) and clinical outcomes (efficacy-evaluable population, n=77) from the phase 2 AUGMENT-101 study in patients with R/R NPM1m AML have been previously reported and demonstrated clinically meaningful responses across a range of prior treatments, including ven, FLT3i, IDH1i, IDH2i, and HSCT (NCT04065399; Arellano et al. EHA 2025. PS1467). Here, we present additional characterization of clinical outcomes, including duration of response (DOR), by prior treatment. METHODS Patients aged ≥30 d with R/R NPM1m AML were eligible to receive revumenib 163 mg (95 mg/m2 if body weight [bw] <40 kg) every 12 h (q12h) with a strong CYP3A4i or 276 mg (160 mg/m2 if bw <40 kg) q12h without a strong CYP3A4i in 28-d cycles. Patients with centrally confirmed NPM1m AML status and ≥5% blasts in bone marrow at baseline within 28 d prior to the start of study treatment were included in the efficacy-evaluable population. Treatment continued until unacceptable toxicity, disease progression, or lack of response after ≤4 cycles. Primary endpoints were rate of CR or CR with partial hematologic recovery (CR+CRh), safety, and tolerability. Secondary endpoints included overall response rate and DOR. Post hoc analysis of DOR by prior treatment was conducted. This analysis was descriptive and not powered to allow statistical comparisons. RESULTS As of September 18, 2024, 77 patients met efficacy-evaluable criteria. Median age was 63 y (range, 11–84 y; 38 patients were ≥65 y). Of these patients, 57 (74.0%) had received prior ven, 31 (40.3%) had prior FLT3i, 5 (6.5%) had prior IDH1i, 5 (6.5%) had prior IDH2i, and 18 (23.4%) had previously undergone HSCT. Overall, the CR+CRh rate was 26.0% (20/77; 95% CI, 16.6%–37.2%) and median duration of CR/CRh was 4.7 mo (95% CI, 2.1–8.2). The CR+CRh rate based on prior treatment was 19.3% (11/57; 10.0%–31.9%) with ven; 12.9% (4/31; 3.6%–29.8%) with FLT3i; 40.0% (2/5; 5.3%–85.3%) with IDH1i; 60.0% (3/5; 14.7%–94.7%) with IDH2i; and 27.8% (5/18; 9.7%–53.5%) with HSCT. Median (95% CI) duration of CR/CRh based on prior treatment was 3.9 mo (1.0–8.2) with ven; 4.3 mo (0.9–NR) with FLT3i; 3.9 mo (NR–NR) with IDH1i; 8.2 mo (NR–NR) with IDH2i; and 5.6 mo (1.8–NR) with HSCT. Safety data from the safety population (N=84) were reported previously; 66 patients (78.6%) experienced a treatment-related AE (TRAE); TRAEs led to treatment discontinuation in 4 patients (4.8%) and death in 1 (1.2%). CONCLUSIONS These findings further characterize outcomes in patients with R/R NPM1m AML treated with revumenib monotherapy in AUGMENT-101. The median DORs by prior treatment were similar to that for the overall population. Given the small subgroup sizes per prior treatment and overlapping confidence intervals, additional data are needed to identify optimal treatment sequences.

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