Preliminary Results of A phase 1 study of the safety and tolerability of the combination of revumenib (REV) with gilteritinib (GILT) in Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) Free

Introduction: REV is an oral targeted menin inhibitor approved for treatment of R/R acute leukemia with KMT2Ar that also has demonstrable clinical activity in patients (pts) with NPM1m AML. REV disrupts a critical protein-protein interaction between menin and KMT2A, leading to downregulation of key HOXA/MEIS1 target genes such as FLT3 and differentiation of leukemic blasts. Kinase-activating FLT3 mutations also occur in roughly half of NPM1m cases. Based upon striking synergy from preclinical AML models with KMT2Ar or NPM1m, there has beensignificant interest in co-targeting of FLT3 and menin. We therefore conducted a phase 1 study to investigate whether REV and the FLT3 inhibitor GILT can be safely combined in R/R AML pts with concurrent FLT3 mutations and genomic abnormalities leading to HOXA/MEIS1 overexpression.

Methods: This is a phase 1, multicenter, dose-escalation study evaluating safety and tolerability with assessment of preliminary efficacy of REV and GILT (NCT06222580). Eligible pts included adults with R/R AML with both a FLT3 mutation and KMT2Ar, NPM1m, or another genomic abnormality reportedly sensitive to menin inhibitors, with adequate cardiac, renal, and hepatic function. A strong CYP3A4 inhibitor for antifungal prophylaxis for ≥24 hours prior to initiation was required. Pts with active CNS involvement, isolated extramedullary disease, or baseline QTcF >450 ms were excluded. A Bayesian optimal interval design guided dose-escalation based on dose-limiting toxicities (DLT) seen up to 28 days from end of cycle 1. Treatment was continued for ongoing response or evidence of clinical benefit. The primary endpoint was to determine the recommended phase 2 dose (RP2D) based upon safety data, with secondary endpoints including response rates, duration of response, and overall survival.

Results: Seven pts were enrolled to 2 dose levels: 3 on dose level (DL) 0 (REV 50mg twice daily, GILT 80mg daily in a 28-day cycle) and 4 on DL1 (REV 113mg twice daily, GILT 120mg daily in a 28-day cycle). 42.9% were male; median age was 57 yrs. Median lines of prior therapy were 1 (range, 1-5); 28.6% had prior allogeneic stem cell transplant (SCT). Majority had FLT3-ITD vs FLT3-TKD (71.4% vs 28.6%) with concurrent NPM1m (71.4%); 14.3% had KMT2A-PTD and 14.3% had NUP98-r. 42.9% of pts had prior menin inhibitors while 28.6% had prior FLT3 inhibitors. Four pts are off treatment and completed a median of 5 cycles (range, 3-8 [72-200 days]). Three pts remain on treatment with a median of 1 cycle (range, 1-8) thus far.

The most common grade ≥3 adverse event among 5 evaluable pts (3 on DL0, 2 on DL1) was febrile neutropenia (n=4). The most common grade ≥3 non-hematologic events were dyspnea (n=2), hypotension (n=2), and QTc prolongation (n=2), with the latter considered a DLT in both cases. In total, 3 pts had QTc prolongation (2 with grade 3 on DL1, 1 with grade 1 on DL0). REV and GILT were held for both pts with grade 3 QTc prolongation and resumed at dose reduction. One pt had successful dose re-escalation after discontinuation of posaconazole without recurrent QTc prolongation. No pts developed arrhythmias. There were no other DLTs. One pt had differentiation syndrome (grade 2 in setting of multifactorial shock).

Four pts discontinued treatment, 3 due to progressive disease and 1 due to infection in setting of morphologic leukemia-free state (MLFS). Three of 7 pts are deceased, related to disease relapse in 2 and infection in 1.

On DL0, 2/3 pts achieved MLFS (1 with negative measurable residual disease (MRD) by PCR) and 1 pt had no response. In DL1, 3/4 pts were evaluated for response. One pt achieved a MRD negative CR by PCR (in the setting of dose reduction due to DLT from QTc prolongation) and has received 8 cycles of therapy with a planned SCT, 1 had partial remission, and 1 had no response with no DLTs at this time. The fourth pt continues C1 at this time; results will be updated at the meeting.

Conclusions: This is the first clinical study evaluating the combination of menin and FLT3 inhibitors for treatment of R/R AML. We have demonstrated that REV can be safely combined with GILT with encouraging preliminary efficacy. QTc prolongation is a DLT when combined with a strong CYP3A4 inhibitor. Additional enrollment is planned in cohorts with varying doses of REV and GILT, without concurrent azoles, to further assess safety and efficacy of this combination therapy.