AUTHORS
Keri Renee Maher, DO, Florian Kuchenbauer2, Maher Abdul-Hay, MD3, Ibrahim Aldoss, MD4, Irina Amitai, MD5, Stéphane de Botton, MD, PhD6, Patrice Chevallier, MD, PhD7, Anne Connor8, Nikki Daskalakis, MD9, Jordi Esteve, MD, PhD10, Matthew Exum, MSN, NP11, Nosha Farhadfar, MD12, Lucille Ferrante, MD13, Jayr Schmidt-Filho, MD14, Charles Foucar, MD15, Stan Gaj, MSc16, Sylvain Garciaz, MD17, Christina Drenberg Guttke, PhD18, Mael Heiblig, MD19, Hsin-An Hou20, Tatsuya Imi21, Elias Jabbour, MD22, Jia Ji23, Anjum Khan24, Steve Knapper25, Rachel Kobos, MD26, Anita J. Kumar27, Manabu Kusakabe28, Min Chul Kwon29, Qian Li, MD30, Yunqing Liu31, Christina Loefgren, MD, PhD32, Ioannis Mantzaris, MD, MS33, Felix Mensah, MD34, Jenny O'Nions, MD35, Lisa O'Rourke36, Kathryn Packman, PhD37, Lixia Pei38, Ulrike Philippar, PhD39, Ana Alfonso-Pierola, MD40, Christian Recher41, Eduardo Rego42, Naa Sackey43, Andre C. Schuh Sr, BSc, MD, FRCPC44, Matthew Schwede, MD45, Emma Searle, MD, PhD46, Thomas Seddon47, Nirav Shah48, Shilpan Shah, MD49, Prathap Nagaraja Shastri, PhD50, Andrew Sochacki, MD51, Richard M. Stone, MD52, Tao Sun53, Trevor Tucker54, Gala Vega55, Maria Vidriales Vicente56, Hui Wei, MD, PhD57, Junichiro Yuda, MD, PhD58, Jianxiang Wang Sr, MD, PhD59
AFFILIATIONS
1 Virginia Commonwealth University, Richmond, Virginia, United States
2 Leukemia/Bone Marrow Transplant Program of British Columbia, Vancouver, Canada
3 Perlmutter Cancer Center at NYU Langone Health, New York, New York, United States
4 City of Hope Comprehensive Cancer Center, Duarte, California, United States
5 Sheba Medical Center, Ramat Gan, Israel
6 Gustave Roussy, Villejuif, France
7 CHU de Nantes Hôtel-Dieu, Nantes, France
8 Johnson & Johnson, Spring House, Pennsylvania, United States
9 Johnson & Johnson, Spring House, Pennsylvania, United States
10 Hospital Clínic de Barcelona, Barcelona, Spain
11 Johnson & Johnson, Spring House, Pennsylvania, United States
12 Sarah Cannon Transplant & Cellular Therapy at Methodist, San Antonio, Texas, United States
13 Johnson & Johnson, Spring House, Pennsylvania, United States
14 A C Camargo Cancer Center, São Paulo, Brazil
15 University of New Mexico, Albuquerque, New Mexico, United States
16 Johnson & Johnson, Beerse, Belgium
17 Institute Paoli-Calmettes, Marseille, France
18 Johnson & Johnson, Spring House, Pennsylvania, United States
19 CHU Lyon Sud, Pierre-Bénite, France
20 National Taiwan University Hospital, Taipei, Taiwan
21 Kanazawa University Hospital, Kanazawa, Japan
22 MD Anderson Cancer Center, Houston, Texas, United States
23 Johnson & Johnson, Spring House, Pennsylvania, United States
24 Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
25 School of Medicine, Cardiff University, Cardiff, United Kingdom
26 Johnson & Johnson, Raritan, New Jersey, United States
27 Johnson & Johnson, Spring House, Pennsylvania, United States
28 Johnson & Johnson, Tokyo, Japan
29 Johnson & Johnson, Beerse, Belgium
30 Johnson & Johnson, Beijing, China
31 Johnson & Johnson, Spring House, Pennsylvania, United States
32 Johnson & Johnson, Raritan, New Jersey, United States
33 Montefiore Medical Center, Bronx, New York, United States
34 Franciscan Health, Indiana Blood and Marrow Transplantation, Indianapolis, Indiana, United States
35 NIHR UCLH Clinical Research Facility, University College London Hospitals NHS Foundation Trust, London, United Kingdom
36 Johnson & Johnson, Spring House, Pennsylvania, United States
37 Johnson & Johnson, Cambridge, Massachusetts, United States
38 Johnson & Johnson, Raritan, New Jersey, United States
39 Johnson & Johnson, Beerse, Belgium
40 Clinical Unversitaria Navarra, Pamplona, Spain
41 Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France
42 Instituto D Or de Pesquisa e Ensino IDOR, São Paulo, Brazil
43 Johnson & Johnson, Spring House, Pennsylvania, United States
44 Princess Margaret Cancer Centre University Health Network, Toronto, Canada
45 Providence Swedish Cancer Institute, Seattle, United States
46 Christie NHS Foundation Trust and University of Manchester, Manchester, United Kingdom
47 The Clatterbridge Cancer Centre, Liverpool, United Kingdom
48 Johnson & Johnson, Spring House, Pennsylvania, United States
49 Houston Methodist Hospital, Houston, Texas, United States
50 Johnson & Johnson, Spring House, Pennsylvania, United States
51 START Midwest, Grand Rapids, Michigan, United States
52 Dana-Farber Cancer Institute, Boston, Massachusetts, United States
53 Johnson & Johnson, Spring House, Pennsylvania, United States
54 Johnson & Johnson, Spring House, Pennsylvania, United States
55 Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
56 Hospital Clínico Universitario de Salamanca, Salamanca, Spain
57 Institute of Hematology and Blood Diseases Hospital, Tianjin, China
58 National Cancer Center Hospital East, Kashiwa, Japan
59 Institute of Hematology and Blood Diseases Hospital, Tianjin, China
ABSTRACT
Background: Despite recent approvals, R/R KMT2A-rearranged (KMT2Ar) or NPM1-mutated (NPM1m) AML remains difficult to treat, underscoring the need for more tolerable and effective targeted therapies. Bleximenib (JNJ-75276617), a potent, selective menin inhibitor, has demonstrated high binding activity and potency in preclinical studies. Phase 1 of the ongoing open-label phase 1/2 cAMeLot-1 study (NCT04811560) of bleximenib monotherapy reported clinical activity and a tolerable safety profile without QTc signal in participants (pts) with R/R KMT2Ar or NPM1m AML. Here we report phase 2 topline efficacy and safety results from the prespecified interim analysis of cAMeLot-1.
Methods: In phase 2, pts with R/R KMT2Ar or NPM1m AML received continuous oral bleximenib at 100 mg twice daily (BID), preceded by a 50 mg BID step-up dose for 14 days, until treatment failure or unacceptable toxicity. Bleximenib was administered without food restrictions or dose adjustments for concomitant strong CYP3A4 inhibitors based on phase 1 data. The primary end point was CR/CRh as assessed by an independent review committee (IRC) per modified ELN 2022 criteria. Safety and demographic data are summarized in the all-treated analysis set, and response data are summarized in the efficacy-evaluable set, both by genetic subtype (Cohort A1-KMT2Ar, Cohort A2-NPM1m).
Results: At the time of analysis, 146 pts received ≥1 dose of bleximenib and had a median follow-up of 8.9 mo in Cohort A1-KMT2Ar (n=67) and 7.9 mo in Cohort A2-NPM1m (n=79). Pts had a median (range) age of 50 (18-82) years in Cohort A1-KMT2Ar and 64 (27-87) years in Cohort A2-NPM1m. Median (range) number of prior lines of therapy was 2 (1-5) in Cohort A1-KMT2Ar and 2 (1-6) in Cohort A2-NPM1m. In Cohort A1-KMT2Ar, 13.4% of pts had ≥3 prior lines and 32.8% had undergone prior hematopoietic stem cell transplant (HSCT). In Cohort A2-NPM1m, 24.1% of pts had ≥3 prior lines and 17.7% had undergone prior HSCT.
In the Cohort A1-KMT2Ar efficacy-evaluable set (n=43), the CR/CRh rate (95% CI) was 51.2% (35.5-66.7%). The median time (range) to CR/CRh was 1.87 (0.9-8.3) mo, and median duration (95% CI) of CR/CRh was 5.62 (2.83-not estimable [NE]) mo.
In the Cohort A2-NPM1m efficacy-evaluable set (n=57), the CR/CRh rate (95% CI) was 40.4% (27.6-54.2%). The median time (range) to CR/CRh was 2.79 (0.8-5.6) mo, and median duration (95% CI) of CR/CRh was 9.23 (2.89-NE) mo.
The most common treatment-emergent adverse events (TEAEs) observed across the genetic subtypes were neutropenia, thrombocytopenia, and anemia, with rates of grade 3-4 events being 37.3%, 31.3%, and 25.4% in Cohort A1-KMT2Ar and 41.8%, 40.5%, and 35.4% in Cohort A2-NPM1m, respectively.
Differentiation syndrome (DS) occurred in 19 (28.4%) pts in Cohort A1-KMT2Ar, including 4 pts with grade 3 DS and 1 pt with grade 4 DS, and 9 (11.4%) pts in Cohort A2-NPM1m, including 5 pts with grade 3 DS. No fatal DS events were observed in either cohort. Median time from first dose to onset of initial DS (range) was 14 (3-30) days in Cohort A1-KMT2Ar and 9 (2-22) days in Cohort A2-NPM1m. DS was effectively managed per protocol guidelines, with no pts discontinuing the study due to DS.
One pt in each cohort, both with cardiovascular comorbidities, had a TEAE of QTc prolongation: grade 1 in Cohort A1-KMT2Ar and grade 3 in Cohort A2-NPM1m; neither pt discontinued bleximenib due to these events. No pts achieving CR/CRh in either cohort have discontinued study treatment due to TEAEs. Updated study results, including key secondary end points, will be available at the time of the congress.
Conclusions: In the cAMeLot-1 phase 2 study, IRC-assessed CR/CRh rates with bleximenib were 51.2% in KMT2Ar and 40.4% in NPM1m R/R AML. Bleximenib was well tolerated with low rates of high-grade DS and no clinical cardiac safety signal. These findings demonstrate strong clinical efficacy with favorable tolerability across menin-dependent AML populations, supporting a compelling benefit-risk profile for bleximenib as a potential best-in-class menin inhibitor and its further evaluation in ongoing phase 3 combination studies in newly diagnosed AML (NCT06852222, NCT07223814).
DISCLOSURES
Keri Renee Maher, DO: No relevant conflicts of interest to declare.