Outcomes after Transplant in Relapsed/Refractory KMT2Ar (MLLr) and mNPM1 (NPM1c) leukemia Patients Achieving Remissions after Menin Inhibition: SNDX-5613 (revumenib) Ph1 Experience

Introduction: In acute leukemia with KMT2A (MLL1)-rearrangement (KMT2Ar) or NPM1 mutation (mNPM1 or NPM1c), menin inhibition by SNDX-5613 (revumenib) disrupts both wild-type KMT2A and KMT2A fusion protein complexes that drive leukemogenesis. Results of the Ph 1 dose escalation portion of the AUGMENT-101 (NCT04065399) trial demonstrated high response rates and manageable safety profile, supporting the initiation of the currently enrolling Phase 2 cohorts at the RP2D of 163 mg q12 hr with strong CYP3A4 inhibitors. Here, we provide an update on r/r KMT2Ar or mNPM1 patients in Arms A and B of the Ph 1 study who proceeded to hematopoietic stem cell transplant (HSCT) in remission (CR+CRh+CRp). We also describe the use of SNDX-5613 in 3 patients as maintenance therapy following HSCT or stem cell boost.

Methods: Arms A and B of the AUGMENT-101 study enrolled patients >= age 30 days with r/r AML in two parallel dose-escalation cohorts: patients not taking (Arm A) or taking (Arm B) strong CYP3A4 inhibitors, with SNDX-5613 dosed orally q12h in continuous 28-day cycles. Patients under 40 kg received BSA-based dosing, with a liquid formulation if needed. Per investigator discretion, patients could proceed to HSCT after discontinuation of SNDX-5613. Patients proceeding to transplant in remission (CR, CRh, CRp) were followed for safety for 30 days after the last dose of SNDX-5613, and for survival/disease assessment until progression. The results of this follow-up are reported here as of the data-cut date of Mar 31, 2022. 3 patients were treated with SNDX-5613 maintenance post-HSCT or stem cell boost on compassionate use single-patient protocols (SPPs). Data is more limited on these subjects with some data derived from investigator reports.

Results: 68 patients were treated on Arm A and B, 60 with r/r KMT2Ar or mNPM1 leukemia. Patients had a median of 4 lines of prior therapy, including 46% having undergone prior HSCT. The overall response rate (CR+CRh+CRp+CRi/MLFS [ORR]) in the efficacy population (KMT2Ar and mNPM1) was 53% (32/60); the rate of CR+CRh+CRp was 38% (23/60) with a CR/CRh rate of 30% (18/60 [95% CI: 18.8, 43.2]). The MRD negative rate among pts with CR/CRh/CRp was 78% (18/23). 12 patients proceeded to HSCT while in remission (CR, CRh, CRp) following SNDX-5613 monotherapy (Table 1). 10/12 (83%) of those patients were MRD negative per local flow cytometry. 7/12 (58%) had received at least 1 HSCT prior to entering the AUGMENT-101 study, with 1 patient having received 2 prior HSCT. 9/12 remained in remission as of the data cut with median follow-up 12.3 months (range 3.2-19.2), and 4 patients had remissions longer than 1 year. No new safety signals were identified. There was one death, due to sepsis, in a patient in remission post HSCT at approximately day 60, following a 3rd HSCT; they had not resumed SNDX-5613 post-transplant.

3 patients were treated with SNDX-5613 maintenance post-HSCT or stem cell boost on SPPs. 1 was among the 12 patients described in Table 1: a 40 yo F with KMT2Ar AML with FLT3 TKD, and 3 prior lines of therapy including 7+3+midostaurin and HSCT. She achieved CRp MRD- with SNDX-5613, proceeded to a second HSCT, followed by 2 cycles of azacytidine for 5 days, and then SNDX-5613 maintenance. She remained in remission at last follow-up almost 10 mo since her CRp. In addition, a 71 yo F with KMT2Ar AML achieved CRh MRD- on AUGMENT-101 and proceeded to a non-myeloablative stem cell boost, followed by SNDX-5613 maintenance, with a 14.5 mo remission. Finally, a 22yo F with KMT2Ar AML with 6 prior lines of therapy including 2 prior HSCTs became CRp MRD- on AUGMENT-101. She then had a molecular relapse and received CPX-351, gemtuzumab, venetoclax, and azacytidine, a 3rd allo-HSCT, and due to persistent positive MRD by flow, she received a donor lymphocyte infusion. She started SNDX-5613 maintenance on Day +111 post 3rd allo-HSCT. She was confirmed MRD negative by flow/PCR after 2 cycles SNDX-5613, and continues in remission more than 1 year.

Conclusion: In SNDX-5613 patients proceeding to transplant, durable remissions occurred across a range of heavily pre-treated patients. In addition to patients achieving CR/CRh, two patients with CRp also had ongoing remissions post-transplant. AUGMENT-101 continues to enroll patients, agnostic of transplant eligibility, with the option for SNDX-5613 post-transplant maintenance.