Top

Published in:

Open Access 01-12-2016 | Review

Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor

Published in: Journal of Hematology & Oncology | Issue 1/2016

Abstract

More and more targeted agents become available for B cell malignancies with increasing precision and potency. The first-in-class Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib, has been in clinical use for the treatment of chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom’s macroglobulinemia. More selective BTK inhibitors (ACP-196, ONO/GS-4059, BGB-3111, CC-292) are being explored. Acalabrutinib (ACP-196) is a novel irreversible second-generation BTK inhibitor that was shown to be more potent and selective than ibrutinib. This review summarized the preclinical research and clinical data of acalabrutinib.

Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101–10.CrossRefPubMed

Fan G, Wang Z, Hao M, Li J. Bispecific antibodies and their applications. J Hematol Oncol. 2015;8(1):1–14.CrossRef

Reusch U, Duell J, Ellwanger K, Herbrecht C, Knackmuss SH, Fucek I, et al. A tetravalent bispecific TandAb (CD19/CD3), AFM11, efficiently recruits T cells for the potent lysis of CD19(+) tumor cells. MAbs. 2015;7(3):584–604.CrossRefPubMed

Suresh T, Lee L, Joshi J, Barta S. New antibody approaches to lymphoma therapy. J Hematol Oncol. 2014;7(1):58.CrossRefPubMedPubMedCentral

Thomas X. Blinatumomab: a new era of treatment for adult ALL? Lancet Oncol. 2014;16(1):6–7.CrossRefPubMed

Wu J, Fu J, Zhang M, Liu D. AFM13: a first-in-class tetravalent bispecific anti-CD30/CD16A antibody for NK cell-mediated immunotherapy. J Hematol Oncol. 2015;8:96.CrossRefPubMedPubMedCentral

Wu J, Fu J, Zhang M, Liu D. Blinatumomab: a bispecific T cell engager (BiTE) antibody against CD19/CD3 for refractory acute lymphoid leukemia. J Hematol Oncol. 2015;8(1):104.CrossRefPubMedPubMedCentral

Cang S, Iragavarapu C, Savooji J, Song Y, Liu D. ABT-199 (venetoclax) and BCL-2 inhibitors in clinical development. J Hematol Oncol. 2015;8(1):129.CrossRefPubMedPubMedCentral

Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311–22.CrossRefPubMed

10.

Rai K. Therapeutic potential of new B cell-targeted agents in the treatment of elderly and unfit patients with chronic lymphocytic leukemia. J Hematol Oncol. 2015;8(1):85.CrossRefPubMedPubMedCentral

11.

Novero A, Ravella PM, Chen Y, Dous G, Liu D. Ibrutinib for B cell malignancies. Experimental Hematology & Oncology. 2014;3(1):1–7.CrossRef

12.

Treon SP, Xu L, Hunter Z. MYD88 mutations and response to ibrutinib in Waldenstrom’s macroglobulinemia. N Engl J Med. 2015;373(6):584–6.CrossRefPubMed

13.

Treon SP, Tripsas CK, Meid K, Warren D, Varma G, Green R, et al. Ibrutinib in previously treated Waldenstrom’s macroglobulinemia. N Engl J Med. 2015;372(15):1430–40.CrossRefPubMed

14.

Cao Y, Yang G, Hunter ZR, Liu X, Xu L, Chen J, et al. The BCL2 antagonist ABT-199 triggers apoptosis, and augments ibrutinib and idelalisib mediated cytotoxicity in CXCR4 Wild-type and CXCR4 WHIM mutated Waldenstrom macroglobulinaemia cells. Br J Haematol. 2015;170(1):134–8.CrossRefPubMed

15.

Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32–42.CrossRefPubMedPubMedCentral

16.

Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369(6):507–16.CrossRefPubMedPubMedCentral

17.

Brown JR, Barrientos JC, Barr PM, Flinn IW, Burger JA, Tran A, et al. The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia. Blood. 2015;125(19):2915–22.CrossRefPubMedPubMedCentral

18.

Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425–37.CrossRefPubMed

19.

Covey T, Barf T, Gulrajani M, Krantz F, van Lith B, Bibikova E, et al. Abstract 2596: ACP-196: a novel covalent Bruton’s tyrosine kinase (Btk) inhibitor with improved selectivity and in vivo target coverage in chronic lymphocytic leukemia (CLL) patients. Cancer Res. 2015;75(15 Supplement):2596.CrossRef

20.

Vidal-Crespo A, Rodríguez V, Matas-Céspedes A, Campos E, López-Guillermo A, Roué G, et al. Abstract 1757: the novel BTK inhibitor CC-292 exerts in vitro and in vivo antitumor activity, interferes with adhesion, cell migration, and synergizes with lenalidomide in MCL models. Cancer Res. 2014;74(19 Supplement):1757.CrossRef

21.

Na L, Zhijian S, Ye L, Mingming G, Yilu Z, Dongping Z, et al. Abstract 2597: BGB-3111 is a novel and highly selective Bruton’s tyrosine kinase (BTK) inhibitor. Cancer Res. 2015;75:2597.CrossRef

22.

Tam C, Grigg AP, Opat S, Ku M, Gilbertson M, Anderson MA, et al. The BTK inhibitor, Bgb-3111, is safe, tolerable, and highly active in patients with relapsed/refractory B-cell malignancies: initial report of a phase 1 first-in-human trial. Blood. 2015;126(23):832.

23.

Walter HS, Rule SA, Dyer MJS, Karlin L, Jones C, Cazin B, et al. A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies. Blood. 2016;127(4):411–9.CrossRefPubMedPubMedCentral

24.

Byrd JC, Harrington B, O'Brien S, Jones JA, Schuh A, Devereux S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):323–32.CrossRefPubMed

25.

Gardner* HL, Harrington* BK, Izumi R, Hamdy A, Kaptein A, Lith BV, et al. Abstract 1744: ACP-196: a second generation Btk inhibitor demonstrates biologic activity in a canine model of B-cell non-Hodgkin lymphoma. Cancer Res. 2014;74(19 Supplement):1744.CrossRef

26.

Harrington BK, Gulrajani M, Covey T, Kaptein A, Van Lith B, Izumi R, et al. ACP-196 is a second generation inhibitor of Bruton tyrosine kinase (BTK) with enhanced target specificity. Blood. 2015;126(23):2908.

27.

Lannutti BJ, Gulrajani M, Krantz F, Bibikova E, Covey T, Jessen K, et al. Abstract 408: ACP-196, an orally bioavailable covalent selective inhibitor of Btk, modulates the innate tumor microenvironment, exhibits antitumor efficacy and enhances gemcitabine activity in pancreatic cancer. Cancer Res. 2015;75(15 Supplement):408.CrossRef

28.

Niemann CU, Montraveta A, Herman SEM, Ingallinera T, Barf T, Colomer D, et al. Abstract 2624: the novel Bruton’s tyrosine kinase inhibitor ACP-196 shows in vivo efficacy against human chronic lymphocytic leukemia cells xenografted to the NSG mouse model. Cancer Res. 2014;74(19 Supplement):2624.CrossRef

29.

Herman SEM, Montraveta A, Niemann CU, Mora-Jensen H, Gulrajani M, Krantz F, et al. The Bruton tyrosine kinase (BTK) inhibitor ACP-196 demonstrates clinical activity in two mouse models of chronic lymphocytic leukemia. Blood. 2015;126(23):2920.

30.

Herman SE, Sun X, McAuley EM, Hsieh MM, Pittaluga S, Raffeld M, et al. Modeling tumor-host interactions of chronic lymphocytic leukemia in xenografted mice to study tumor biology and evaluate targeted therapy. Leukemia. 2013;27(12):2311–21.CrossRefPubMedPubMedCentral

31.

Rai KR, Barrientos JC. Movement toward optimization of CLL therapy. N Engl J Med. 2014;370(12):1160–2.CrossRefPubMed

32.

Yang Q, Modi P, Newcomb T, Queva C, Gandhi V. Idelalisib: first-in-class PI3K delta inhibitor for the treatment of chronic lymphocytic leukemia, small lymphocytic leukemia, and follicular lymphoma. Clin Cancer Res. 2015;21(7):1537–42.CrossRefPubMed

33.

Iragavarapu C, Mustafa M, Akinleye A, Furqan M, Mittal V, Cang S, et al. Novel ALK inhibitors in clinical use and development. J Hematol Oncol. 2015;8(1):17.CrossRefPubMedPubMedCentral

34.

Parikh K, Cang S, Sekhri A, Liu D. Selective inhibitors of nuclear export (SINE)—a novel class of anti-cancer agents. J Hematol Oncol. 2014;7(1):78.CrossRefPubMedPubMedCentral

35.

Das A, Wei G, Parikh K, Liu D. Selective inhibitors of nuclear export (SINE) in hematological malignancies. Exp Hematol Oncol. 2015;4:7.CrossRefPubMedPubMedCentral

36.

Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202–8.CrossRefPubMed

37.

Zhao X, Rajasekaran N, Reusch U, Weichel M, Ellwanger K, Marschner J-P, et al. In vitro and in vivo characterization of CD19/CD3 Tandab AFM11 and CD19/CD16A Tandab AFM12 targeting NHL. Blood. 2015;126(23):2763.

Title: Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor
Publication date: 01-12-2016
Published in: Journal of Hematology & Oncology / Issue 1/2016
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-016-0250-9

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2016

Immune biomarkers of treatment failure for a patient on a phase I clinical trial of pembrolizumab plus radiotherapy

The novel thiosemicarbazone, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), inhibits neuroblastoma growth in vitro and in vivo via multiple mechanisms

Pharmacological inhibition of LSD1 for the treatment of MLL-rearranged leukemia

LncRNAs H19 and HULC, activated by oxidative stress, promote cell migration and invasion in cholangiocarcinoma through a ceRNA manner

l-asparaginase-based regimens followed by allogeneic hematopoietic stem cell transplantation improve outcomes in aggressive natural killer cell leukemia

Keynote webinar | Spotlight on antibody–drug conjugates in cancer