Menin Inhibition With Revumenib for <i>KMT2A</i>-Rearranged Relapsed or Refractory Acute Leukemia (AUGMENT-101)-Reference-Cited by-同舟云学术

Menin Inhibition With Revumenib for KMT2A-Rearranged Relapsed or Refractory Acute Leukemia (AUGMENT-101)

Published:2024-08-09 Issue: Volume: Page:
ISSN:0732-183X
Container-title:Journal of Clinical Oncology
language:en
Short-container-title:JCO

Author:

Issa Ghayas C.¹^ORCID,Aldoss Ibrahim²,Thirman Michael J.³^ORCID,DiPersio John⁴^ORCID,Arellano Martha⁵,Blachly James S.⁶^ORCID,Mannis Gabriel N.⁷,Perl Alexander⁸^ORCID,Dickens David S.⁹^ORCID,McMahon Christine M.¹⁰,Traer Elie¹¹^ORCID,Zwaan C. Michel¹²^ORCID,Grove Carolyn S.¹³^ORCID,Stone Richard¹⁴^ORCID,Shami Paul J.¹⁵,Mantzaris Ioannis¹⁶,Greenwood Matthew¹⁷^ORCID,Shukla Neerav¹⁸^ORCID,Cuglievan Branko¹,Kovacsovics Tibor¹⁹,Gu Yu²⁰,Bagley Rebecca G.²⁰,Madigan Kate²⁰,Chudnovsky Yakov²⁰,Nguyen Huy Van²⁰,McNeer Nicole²⁰,Stein Eytan M.¹⁸^ORCID,Wei Andrew,Fleming Shaun,Sabins Himalee,Aldoss Ibrahim,Kovacsovics Tibor,Stone Richard,Arellano Martha,Patel Manish,Talati Chetasi,Chen Jing,Nachmias Boaz,Heiblig Mael,Fernandez Pau Montesios,Arnan-Sangerman Montserrat,Stein Eytan M.,Mantzaris Ioannis,Blachly James S.,Traer Elie,Zwaan C. Michael,Wolach Ofir,Marconi Giovanni,Bajel Ashish,Grove Carolyn S.,Mannis Gabriel N.,Schuh Andre,Thirman Michael,Byrd John,McMahon Christine M.,Dickens David S.,Perl Alexander,Greenwood Matthew,Issa Ghayas C.,Whitlock James,Shami Paul J.,DiPersio John

Affiliation:

1. Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

2. Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA

3. Biological Sciences Division, The University of Chicago Medicine, Chicago, IL

4. John T. Milliken Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, MO

5. Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA

6. Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH

7. Division of Hematology, Stanford University School of Medicine, Stanford, CA

8. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

9. University of Iowa Stead Family Children's Hospital, Iowa City, IA

10. UCHealth Blood Disorders and Cell Therapies Center, University of Colorado School of Medicine, Aurora, CO

11. Knight Cancer Institute, Oregon Health & Science University, Portland, OR

12. Princess Máxima Center for Pediatric Oncology, Utrecht, and Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands

13. Department of Haematology, Sir Charles Gairdner Hospital, Nedlands, Australia

14. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA

15. University of Utah Huntsman Cancer Institute, Salt Lake City, UT

16. Department of Oncology, Montefiore Einstein Comprehensive Cancer Center, Bronx, NY

17. Department of Haematology, Royal North Shore Hospital, The University of Sydney, Sydney, New South Wales, Australia

18. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY

19. City of Hope Phoenix, Goodyear, AZ

20. Syndax Pharmaceuticals, Inc, Waltham, MA

Abstract

PURPOSE Revumenib, an oral, small molecule inhibitor of the menin-lysine methyltransferase 2A (KMT2A) interaction, showed promising efficacy and safety in a phase I study of heavily pretreated patients with KMT2A-rearranged ( KMT2Ar) acute leukemia. Here, we evaluated the activity of revumenib in individuals with relapsed/refractory (R/R) KMT2Ar acute leukemia. METHODS AUGMENT-101 is a phase I/II, open-label, dose-escalation and expansion study of revumenib conducted across 22 clinical sites in five countries (ClinicalTrials.gov identifier: NCT04065399 ). We report results from the phase II, registration-enabling portion. Individuals age ≥30 days with R/R KMT2Ar acute leukemia or with AML and nucleophosmin 1 ( NPM1) mutation were enrolled. Revumenib was administered once every 12 hours, at 163 mg (95 mg/m2 if weight <40 kg) with a strong cytochrome P450 inhibitor, in 28-day cycles. The primary end points were the rate of complete remission (CR) or CR with partial hematologic recovery (CR + CRh) and safety. At a prespecified interim analysis, safety was assessed in all KMT2Ar treated patients; efficacy was assessed in those with centrally confirmed KMT2Ar. The separate NPM1 cohort of the trial is ongoing. RESULTS From October 1, 2021, to July 24, 2023, N = 94 patients (median [range] age, 37 [1.3-75] years) were treated. Grade ≥3 adverse events included febrile neutropenia (37.2%), differentiation syndrome (16.0%), and QTc prolongation (13.8%). In the efficacy-evaluable patients (n = 57), the CR + CRh rate was 22.8% (95% CI, 12.7 to 35.8), exceeding the null hypothesis of 10% ( P = .0036). Overall response rate was 63.2% (95% CI, 49.3 to 75.6), with 15 of 22 patients (68.2%) having no detectable residual disease. CONCLUSION Revumenib led to high remission rates with a predictable safety profile in R/R KMT2Ar acute leukemia. To our knowledge, this trial represents the largest evaluation of a targeted therapy for these patients.

Publisher

American Society of Clinical Oncology (ASCO)

Link

https://ascopubs.org/doi/pdfdirect/10.1200/JCO.24.00826

Reference26 articles.

1. Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia

2. Outcome of Infants Younger Than 1 Year With Acute Lymphoblastic Leukemia Treated With the Interfant-06 Protocol: Results From an International Phase III Randomized Study

3. Outcome of relapsed infant acute lymphoblastic leukemia treated on the interfant-99 protocol

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

5. Predictors of outcomes in adults with acute myeloid leukemia and KMT2A rearrangements