The BTK inhibitor ibrutinib is well tolerated and active in B-cell cancers.

  • Major finding: The BTK inhibitor ibrutinib is well tolerated and active in B-cell cancers.

  • Approach: The optimal biologic dose of ibrutinib was determined based on BTK active site occupancy.

  • Impact: Inhibition of BTK alone can block active BCR signaling in multiple B-cell malignancies.

Aberrant B-cell antigen receptor (BCR) signaling has been implicated in the development of mature B-cell malignancies. Bruton tyrosine kinase (BTK) is a key effector molecule in antigen-stimulated BCR signaling and represents an attractive therapeutic target due to its restricted expression in B lymphocytes. Ibrutinib has been developed as an orally bioavailable, irreversible BTK inhibitor that binds the kinase active site to block BCR signaling. Advani and colleagues report the results of a phase I trial of ibrutinib in 56 patients with relapsed or refractory B-cell non-Hodgkin lymphomas or B-cell chronic lymphocytic leukemia (CLL). Ibrutinib occupancy of the BTK active site in peripheral blood mononuclear cells was determined by assaying the ability of a fluorescent probe to bind BTK before and during ibrutinib treatment. Ibrutinib blocked the probe from binding to BTK starting 4 hours after treatment initiation and throughout the entire 4-week treatment cycle, indicating that ibrutinib-mediated inhibition of BTK is durable and complete. Importantly, BTK occupancy was ibrutinib dose dependent, allowing the authors to determine an optimal biologic dose. A maximum tolerated dose was not reached, and ibrutinib generally caused only grade 1 or 2 adverse events, likely due to the restricted expression of BTK and the rapid absorption and elimination of ibrutinib. Strikingly, 60% of evaluable patients achieved an objective response, and 16% of patients had complete responses. Of note, 3 of the 9 patients who experienced disease progression had been treated with a lower dose of ibrutinib that was not sufficient for complete BTK occupancy, further linking BTK occupancy to ibrutinib efficacy. Together, these findings underscore the central role of BTK in the growth and survival of various B-cell malignancies and support further study of ibrutinib in larger clinical trials.

Advani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol 2012 Oct 8 [Epub ahead of print].