Authored by Ann Liu, PhD
Medically Reviewed by Ed Ratner, MD
The Bottom Line:
A phase 2 clinical trial is testing the efficacy of IRAK-4 inhibitor emavusertib combined with BTK inhibitor zanubrutinib in patients with CLL.
Background:
The B-cell receptor pathway sends pro-survival messages to chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL) cells, leading to their accumulation in blood, bone marrow, lymph nodes, and spleen. Blocking the B-cell receptor pathway with BTK inhibitors (BTKi) is very effective for treating CLL / SLL. However, BTKi must be taken continuously to suppress this pathway. If stopped, isolated CLL cells can then again proliferate and accumulate. In addition, mutations in the CLL cells can block the effectiveness of BTKi medications. This finding indicates that while the B-cell receptor is very important, it is not the only way that CLL cells get survival and proliferation signals.
Emavusertib is an experimental subcutaneous drug that inhibits interleukin-1 receptor-associated kinase 4 (IRAK-4), a protein in the toll-like receptor 9 (TLR9) pathway. Researchers hypothesize that blocking IRAK-4 will more completely shut off pro-survival signaling by inhibiting nuclear factor-kappa B (NF-kB) signaling, which is important for the expression of inflammatory cytokines and certain pro-survival factors. Emavusertib has already been through phase 1 safety testing and has shown activity in acute myeloid leukemia and some types of non-Hodgkin lymphoma.
In the interview, Dr. Jennifer Woyach from The Ohio State University discusses an ongoing study of emavusertib combined with a BTKi for patients with CLL. By combining two drugs that block complementary pathways, the hope is that CLL survival signals will be completely inhibited, and patients will have deep and prolonged responses with undetectable measurable residual disease (uMRD).
Methods and Participants:
- This is a phase 2 clinical trial that plans on enrolling 108 patients with CLL.
- The primary objective of the study is to assess the anticancer activity of emavusertib in combination with zanubrutinib in patients with CLL.
- Cohort 1 is currently enrolling patients with CLL who have been on zanubrutinib for at least one year and are in a partial response.
- Cohort 2 will be enrolling patients with CLL who have been treated with zanubrutinib and responded but are now starting to progress.
- Patients in both cohorts will have monthly emavusertib (at two different dose levels) added to their current zanubrutinib therapy.
- The primary outcomes are uMRD rate and overall response rate.
- Patients will be in the study for up to two years.
- The study is currently enrolling at sites in the US, Italy, and Spain.
Conclusions:
This is one of a number of studies examining the deferred addition of a second drug to a BTKi to allow transition from continuous to time-limited treatment, called consolidation therapy. This is the first study to test the combination of an IRAK-4 inhibitor and a BTKi in CLL. Researchers hope that by blocking two complementary pathways, which are key to CLL survival and proliferation, they will be able to get patients into deeper remissions with the potential for fixed-duration treatment. If you are interested in participating in this study, available at six U.S. sites, more information can be found here: A Study of Emavusertib + An Approved Bruton Tyrosine Kinase Inhibitor (BTKi) in Participants With Chronic Lymphocytic Leukemia (CLL) and Other B-cell Malignancies
Links and Resources:
Watch the interview here:
