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

Program: Oral and Poster Abstracts
Type: Oral
Session: 723. Allogeneic Transplantation: Long-term Follow-up and Disease Recurrence II
Hematology Disease Topics & Pathways:
clinical trials, Research, Clinical Research
Saturday, December 10, 2022: 4:45 PM

Ghayas C. Issa, MD1, Branko Cuglievan, MD2*, Eytan Stein, MD3, Martha L. Arellano, MD4, Andrius Zucenka, MD5*, Nandita Khera, MD, MPH6, Richard M. Stone, MD7, Michael J. Thirman, MD8, John F. DiPersio, MD, PhD9, Nicole Karras, MD10*, Yu Gu, PhD11*, Rebecca G. Bagley, MA11*, Galit Rosen, MD11, David Tamang11*, Kimberly Dishman, NP11*, Sushama Scalera, MD11*, Michael L. Meyers, MD, PhD11*, Kate Madigan, MD11*, Nicole McNeer, MD, PhD11 and Ibrahim Aldoss, MD12

1Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX
2Division of Pediatric Hematology Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
3Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
4Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA
5Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania
6Division of Hematology/Oncology, Mayo Clinic, Phoenix, AZ
7Center for Leukemia, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
8Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL
9Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, MO
10Department of Pediatrics, City of Hope National Medical Center, Duarte, CA
11Syndax Pharmaceuticals, Inc., Waltham, MA
12City of Hope, Duarte, CA

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.

Disclosures: Issa: Novartis, Kura Oncology, Nuprobe: Consultancy; Celgene, Kura Oncology, Syndax, Merck, Cullinan and Novartis: Research Funding. Stein: Astellas Pharmaceutical, Agios Pharmaceuticals, and Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; PinotBio, Bristol Myers Squibb, Jazz Pharmaceuticals, Foghorn Therapeutics, Blueprint Medicines, Gilead Sciences, Janssen Pharmaceuticals: Consultancy; Auron Therapeutics: Current equity holder in private company; Daiichi-Sankyo, Celgene Pharmaceuticals, and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen, AbbVie, Seattle Genetics, and Biotheryx: Consultancy; Syndax: Consultancy, Research Funding; PTC Therapeutics and Syros: Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding. Arellano: Kite, a Gilead Company: Consultancy, Research Funding; Syndax Pharmaceuticals: Consultancy. Zucenka: Astellas: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel Expenses; Abbvie: Consultancy, Honoraria, Other: Travel Expenses; Pfizer: Consultancy. Khera: Incyte: Consultancy; Optum: Honoraria. Stone: BerGenBio: Consultancy; Epizyme: Consultancy; BMS: Consultancy; Syndax: Consultancy; OncoNova: Consultancy; Jazz: Consultancy; Kura Oncology: Consultancy; Novartis: Consultancy; GSK: Consultancy; Gemoab: Consultancy; Astellas: Consultancy; Syntrix: Consultancy; Syros: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Innate: Consultancy; Elevate Bio: Consultancy; Boston Pharmaceuticals: Consultancy; Aprea: Consultancy; Apteva: Consultancy; Arog: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Actinium: Consultancy; Foghorn Therapeutics: Consultancy. Thirman: AbbVie, AstraZeneca, Celgene,Janssen, Pharmacyclics, Roche/Genentech: Consultancy; AbbVie,Gilead Sciences,Janssen,Merck,Pharmacyclics, Syndax, TG Therapeutics, Tolero Pharmaceuticals.: Consultancy, Research Funding. DiPersio: NeoImmune Tech: Research Funding; Amphivena Therapeutics: Research Funding; hC Bioscience, Inc.: Membership on an entity's Board of Directors or advisory committees; RiverVest Venture Partners: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Research Funding; Magenta Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; WUGEN: Current equity holder in private company, Research Funding; BioLineRx, Ltd.: Research Funding; Macrogenics: Research Funding; CAR-T cell Product with Washington University and WUGEN: Patents & Royalties; VLA-4 Inhibitor with Washington University and Magenta Therapeutics: Patents & Royalties. Gu: Syndax: Current Employment. Bagley: Syndax: Current Employment. Rosen: Syndax: Current Employment. Tamang: Syndax: Current Employment. Dishman: Syndax: Current Employment. Scalera: Syndax: Current Employment. Meyers: Syndax: Current Employment. Madigan: Syndax: Current Employment. McNeer: Syndax: Current Employment. Aldoss: Sobi: Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; MacroGenics: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Autolus: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

*signifies non-member of ASH