Mechanism of Action Magnifier – 2016 Desk Reference

← Back to Supplement

Ibrutinib: an Inhibitor of Bruton’s Tyrosine Kinase

B cells circulate between multiple sites in the body during their normal life cycle, and these B cells rely on cues from the support of microenvironments to promote proper development, maturation, and function.1 Chemotaxis to, and adhesion within, proliferative microenvironments, as well as intracellular prosurvival signaling that promotes growth and prevents cell death, are necessary for normal B-cell function and survival.1 Constitutive activation of B-cell receptor signaling appears to be essential for the survival and proliferation of malignant B cells, an observation that has led to the design of inhibitors of B-cell receptor–associated kinases.2 In B-cell malignancies, some normal biologic processes become dysregulated, resulting in increased proliferation, trafficking, and adhesion of malignant B cells within supportive microenvironments.1 Signaling through chemokine receptors mediates B-cell trafficking, chemotaxis, and adhesion to these proliferative niches.3,4 Additionally, certain malignant B cells may have increased prosurvival signaling through the B-cell antigen receptor (BCR), which is fundamental to B-cell activation.3,4

Bruton’s tyrosine kinase (BTK) is one of the essential effectors of all of these processes.5 BTK is a signaling molecule of the BCR and cytokine receptor pathways.6 BTK’s role in signaling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion.6

Compelling evidence suggests that crosstalk with accessory stromal cells in specialized tissue microenvironments, such as the bone marrow and secondary lymphoid organs, favors disease progression in hematologic cancers by promoting malignant B-cell growth and drug resistance.7 Therefore, disrupting the crosstalk between malignant B cells and their milieu is an attractive strategy for treating selected mature B-cell malignancies.7,8

Ibrutinib (PCI-32765) is a selective and irreversible small molecule inhibitor of BTK that inhibits BCR signaling in human B cells via specific active-site occupancy.9 Ibrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity.6,10,11

In vivo and in vitro studies* have shown that ibrutinib affects 3 key malignant B-cell processes (Figure): inhibits proliferation and survival, inhibits adhesion (binding to other cells in the microenvironment), and modulates chemotaxis (migration of B cells in and out of lymphatic tissue).6,9,12-15 In addition, data suggest that ibrutinib decreases interactions between malignant cells and the microenvironment.



Ibrutinib is indicated for the treatment of 6:

  • Patients with chronic lymphocytic leukemia (CLL) who have received at least 1 prior therapy
  • Patients with CLL with 17p deletion
  • Patients with mantle cell lymphoma who have received at least 1 prior therapy
    • Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials
  • Patients with Waldenström’s macroglobulinemia.

*Correlation to clinical effect has not been established.

References

  1. Parmar S, Patel K, Pinilla-Ibarz J. Ibrutinib (imbruvica): a novel targeted therapy for chronic lymphocytic leukemia. P T. 2014;39:483-519.
  2. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369:507-516.
  3. Danilov AV. Targeted therapy in chronic lymphocytic leukemia: past, present, and future. Clin Ther. 2013;35:1258-1270.
  4. Wiestner A. Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia. Blood. 2012;120:4684-4691.
  5. Buggy JJ, Elias L. Bruton tyrosine kinase (BTK) and its role in B-cell malignancy. Int Rev Immunol. 2012;31:119-132.
  6. Imbruvica [package insert]. Sunnyvale, CA: Pharmacyclics, Inc; 2015.
  7. Burger JA, Ghia P, Rosenwald A, et al. The microenvironment in mature B-cell malignancies: a target for new treatment strategies. Blood. 2009;114:3367-3375.
  8. Herishanu Y, Pérez-Galán P, Liu D, et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood. 2011;117:563-574.
  9. Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci U S A. 2010;107:13075-13080.
  10. Ponader S, Balasubramanian S, Pham LV, et al. Activity of Bruton’s tyrosine kinase (Btk) inhibitor PCI-32765 in mantle cell lymphoma (MCL) identifies Btk as a novel therapeutic target. Presented at: ASH Annual Meeting; December 12, 2011; San Diego, CA. Abstract 3688.
  11. Wang L, Martin P, Blum KA, et al. The Bruton’s tyrosine kinase inhibitor PCI-32765 is highly active as single-agent therapy in previously-treated mantle cell lymphoma (MCL): preliminary results of a phase II trial. Presented at: ASH Annual Meeting; December 12, 2011; San Diego, CA. Abstract 442.
  12. Chang BY, Francesco M, Steggerda S, et al. Ibrutinib inhibits malignant cell adhesion and migration and reduces tumor burden in lymph node and bone marrow in a murine model of mantle cell dissemination and progression. Presented at: AARC 104th Annual Meeting 2013; April 6-10, 2013; Washington, DC. Abstract 923.
  13. Chang BY, Francesco M, De Rooij MFM, et al. Egress of CD19(+)CD5(+) cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients. Blood. 2013;122:2412-2424.
  14. Cinar M, Hamedani F, Mo Z, et al. Bruton tyrosine kinase is commonly overexpressed in mantle cell lymphoma and its attenuation by Ibrutinib induces apoptosis. Leuk Res. 2013:37;1271-1277.
  15. Ponader S, Chen SS, Buggy JJ, et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood. 2012;119:1182-1189.
Uncategorized - March 18, 2019

Next-Generation Sequencing Testing in Oncology

Following the advent of molecularly targeted agents, and more recently, immunotherapy, over the past few decades, we have witnessed dramatic changes in the treatment paradigms for many types of cancer.

Lung Cancer, Web Exclusives - May 29, 2019

Personalizing Immunotherapy in NSCLC Using PD-L1 and Tumor Mutation Burden as Biomarkers

Tumor expression of PD-L1 has consistently predicted ­response and survival outcomes in non–small-cell lung cancer (NSCLC), whereas the role of PD-L1 in immune cells is unclear, said ­Edward B. Garon, MD, Director, Thoracic Oncology Program, David Geffen School of Medicine, University of California, Los Angeles, at the 2019 ASCO-SITC Clinical Immuno-Oncology Symposium.