First-in-Human Study of the Reversible BTK Inhibitor Nemtabrutinib in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia and B-Cell Non-Hodgkin Lymphoma

被引：31

作者：

Woyach, Jennifer A. ^{[1
,8
]}

Stephens, Deborah M. ^{[2
]}

Flinn, Ian W. ^{[3
]}

Bhat, Seema A. ^{[1
]}

Savage, Ronald E. ^{[4
]}

Chai, Feng ^{[4
]}

Eathiraj, Sudharshan ^{[4
]}

Reiff, Sean D. ^{[1
]}

Muhowski, Elizabeth M. ^{[1
]}

Granlund, Lindsey ^{[4
]}

Szuszkiewicz, Lyndsey ^{[1
]}

Wang, Wayne ^{[5
]}

Schwartz, Brian ^{[4
]}

Ghori, Razi ^{[6
]}

Farooqui, Mohammed Z. H. ^{[6
]}

Byrd, John C. ^{[7
]}

机构：

[1] Ohio State Univ, Columbus, OH USA

[2] Huntsman Canc Inst, Salt Lake City, UT USA

[3] Sarah Cannon Res Inst, Nashville, TN USA

[4] ArQule Inc, Burlington, MA USA

[5] Veristat LLC, Southborough, MA USA

[6] Merck & Co Inc, Rahway, NJ USA

[7] Univ Cincinnati, Coll Med, Dept Internal Med, Cincinnati, OH USA

[8] Ohio State Univ, Comprehens Canc Ctr, Columbus, OH 43210 USA

来源：

CANCER DISCOVERY | 2024年 / 14卷 / 01期

关键词：

IBRUTINIB; RESISTANCE; MUTATION; THERAPY;

D O I：

10.1158/2159-8290.CD-23-0670

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Nemtabrutinib, a reversible inhibitor of both wild-type and C481-mutated BTK, demonstrates safety and preliminary efficacy in patients with relapsed or refractory B cell malignancies. Nemtabrutinib is an orally bioavailable, reversible inhibitor of Bruton tyrosine kinase (BTK) and C481S mutant BTK. We evaluated the safety, pharmacology, and antitumor activity of nemtabrutinib in relapsed/refractory hematologic malignancies. Forty-eight patients with chronic lymphocytic leukemia (CLL), B-cell non-Hodgkin lymphoma (NHL), or Waldenstrom macroglobulinemia (WM), relapsed/refractory after >= 2 prior therapies were enrolled in the open-label, single-arm, phase I MK-1026-001 study (NCT03162536) to receive nemtabrutinib 5 to 75 mg once daily in 28-day cycles. Dose finding progressed using a 3 + 3 dose escalation design. Primary endpoints were safety and the recommended phase II dose (RP2D). Among 47 treated patients, 29 had CLL, 17 had NHL, and 1 had WM. Grade >= 3 treatment-emergent adverse events occurred in 37 (89%), most commonly neutropenia (11; 23.4%), febrile neutropenia (7; 14.9%), and pneumonia (7; 14.9%). The RP2D was 65 mg daily. An overall response rate of 75% was observed in patients with CLL at 65 mg daily.Significance: This first-in-human phase I study demonstrates the safety and preliminary efficacy of nemtabrutinib in patients with relapsed/refractory B-cell malignancies. These data support further exploration of nemtabrutinib in larger clinical studies. This article is featured in Selected Articles from This Issue, p. 5Significance: This first-in-human phase I study demonstrates the safety and preliminary efficacy of nemtabrutinib in patients with relapsed/refractory B-cell malignancies. These data support further exploration of nemtabrutinib in larger clinical studies. This article is featured in Selected Articles from This Issue, p. 5

引用

页码：66 / 75

页数：10

共 25 条

[1] High Sensitivity Testing Shows Multiclonal Mutations in Patients with CLL Treated with BTK Inhibitor and Lack of Mutations in Ibrutinib-Naive Patients [J].

Albitar, Adam ;

Ma, Wanlong ;

De Dios, Ivan ;

Estrella, Jeffrey ;

Farooqui, Mohammed ;

Wiestner, Adrian ;

Albitar, Maher .

BLOOD, 2015, 126 (23)

[2] Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia [J].

Brown, J. R. ;

Eichhorst, B. ;

Hillmen, P. ;

Jurczak, W. ;

Kazmierczak, M. ;

Lamanna, N. ;

O'Brien, S. M. ;

Tam, C. S. ;

Qiu, L. ;

Zhou, K. ;

Simkovic, M. ;

Mayer, J. ;

Gillespie-Twardy, A. ;

Ferrajoli, A. ;

Ganly, P. S. ;

Weinkove, R. ;

Grosicki, S. ;

Mital, A. ;

Robak, T. ;

Osterborg, A. ;

Yimer, H. A. ;

Salmi, T. ;

Wang, M. -D. -Y. ;

Fu, L. ;

Li, J. ;

Wu, K. ;

Cohen, A. ;

Shadman, M. .

NEW ENGLAND JOURNAL OF MEDICINE, 2023, 388 (04) :319-332

[3] Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia [J].

Burger, J. A. ;

Tedeschi, A. ;

Barr, P. M. ;

Robak, T. ;

Owen, C. ;

Ghia, P. ;

Bairey, O. ;

Hillmen, P. ;

Bartlett, N. L. ;

Li, J. ;

Simpson, D. ;

Grosicki, S. ;

Devereux, S. ;

McCarthy, H. ;

Coutre, S. ;

Quach, H. ;

Gaidano, G. ;

Maslyak, Z. ;

Stevens, D. A. ;

Janssens, A. ;

Offner, F. ;

Mayer, J. ;

O'Dwyer, M. ;

Hellmann, A. ;

Schuh, A. ;

Siddiqi, T. ;

Polliack, A. ;

Tam, C. S. ;

Suri, D. ;

Cheng, M. ;

Clow, F. ;

Styles, L. ;

James, D. F. ;

Kipps, T. J. ;

Keating, Michael ;

Jen, Jie ;

Jindra, Pavel ;

Simkovic, Martin ;

Braester, Andrei ;

Ruchlemer, Rosa ;

Foa, Roberto ;

Semenzato, Gianpietro ;

Hawkins, Timothy ;

Atanasio, Carolina Moreno ;

Demirkan, Fatih ;

Kaynar, Leylagul ;

Pylypenko, Halyna ;

Fox, Christopher ;

Thirman, Michael ;

Campbell, Philip .

NEW ENGLAND JOURNAL OF MEDICINE, 2015, 373 (25) :2425-2437

[4] Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study [J].

Burger, Jan A. ;

Barr, Paul M. ;

Robak, Tadeusz ;

Owen, Carolyn ;

Ghia, Paolo ;

Tedeschi, Alessandra ;

Bairey, Osnat ;

Hillmen, Peter ;

Coutre, Steven E. ;

Devereux, Stephen ;

Grosicki, Sebastian ;

McCarthy, Helen ;

Simpson, David ;

Offner, Fritz ;

Moreno, Carol ;

Dai, Sandra ;

Lal, Indu ;

Dean, James P. ;

Kipps, Thomas J. .

LEUKEMIA, 2020, 34 (03) :787-798

[5] Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia [J].

Byrd, J. C. ;

Brown, J. R. ;

O'Brien, S. ;

Barrientos, J. C. ;

Kay, N. E. ;

Reddy, N. M. ;

Coutre, S. ;

Tam, C. S. ;

Mulligan, S. P. ;

Jaeger, U. ;

Devereux, S. ;

Barr, P. M. ;

Furman, R. R. ;

Kipps, T. J. ;

Cymbalista, F. ;

Pocock, C. ;

Thornton, P. ;

Caligaris-Cappio, F. ;

Robak, T. ;

Delgado, J. ;

Schuster, S. J. ;

Montillo, M. ;

Schuh, A. ;

de Vos, S. ;

Gill, D. ;

Bloor, A. ;

Dearden, C. ;

Moreno, C. ;

Jones, J. J. ;

Chu, A. D. ;

Fardis, M. ;

McGreivy, J. ;

Clow, F. ;

James, D. F. ;

Hillmen, P. .

NEW ENGLAND JOURNAL OF MEDICINE, 2014, 371 (03) :213-223

[6] Functional characterization of BTKC481S mutation that confers ibrutinib resistance: exploration of alternative kinase inhibitors [J].

Cheng, S. ;

Guo, A. ;

Lu, P. ;

Ma, J. ;

Coleman, M. ;

Wang, Y. L. .

LEUKEMIA, 2015, 29 (04) :895-900

[7] Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification [J].

Cheson, Bruce D. ;

Fisher, Richard I. ;

Barrington, Sally F. ;

Cavalli, Franco ;

Schwartz, Lawrence H. ;

Zucca, Emanuele ;

Lister, T. Andrew .

JOURNAL OF CLINICAL ONCOLOGY, 2014, 32 (27) :3059-+

[8] ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia [J].

Ghia, Paolo ;

Pluta, Andrzej ;

Wach, Malgorzata ;

Lysak, Daniel ;

Kozak, Tomas ;

Simkovic, Martin ;

Kaplan, Polina ;

Kraychok, Iryna ;

Illes, Arpad ;

de la Serna, Javier ;

Dolan, Sean ;

Campbell, Phillip ;

Musuraca, Gerardo ;

Jacob, Abraham ;

Avery, Eric ;

Lee, Jae Hoon ;

Liang, Wei ;

Patel, Priti ;

Quah, Cheng ;

Jurczak, Wojciech .

JOURNAL OF CLINICAL ONCOLOGY, 2020, 38 (25) :2849-+

[9] iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL [J].

Hallek, Michael ;

Cheson, Bruce D. ;

Catovsky, Daniel ;

Caligaris-Cappio, Federico ;

Dighiero, Guillermo ;

Doehner, Hartmut ;

Hillmen, Peter ;

Keating, Michael ;

Montserrat, Emili ;

Chiorazzi, Nicholas ;

Stilgenbauer, Stephan ;

Rai, Kanti R. ;

Byrd, John C. ;

Eichhorst, Barbara ;

O'Brien, Susan ;

Robak, Tadeusz ;

Seymour, John F. ;

Kipps, Thomas J. .

BLOOD, 2018, 131 (25) :2745-2760

[10] PLCG2 C2 domain mutations co-occur with BTK and PLCG2 resistance mutations in chronic lymphocytic leukemia undergoing ibrutinib treatment [J].

Jones, D. ;

Woyach, J. A. ;

Zhao, W. ;

Caruthers, S. ;

Tu, H. ;

Coleman, J. ;

Byrd, J. C. ;

Johnson, A. J. ;

Lozanski, G. .

LEUKEMIA, 2017, 31 (07) :1645-1647

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