Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, MDCM )retired), MSEd
The Bottom Line:
Preclinical research shows that rocbrutinib inhibits BTK and B-cell receptor pathway signaling even in the presence of BTK mutations commonly seen in CLL.
Who Performed the Research and Where Was it Presented:
Dr. Jennifer Woyach from the Ohio State University and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting in 2025.
Background:
Bruton tyrosine kinase inhibitors (BTKi) have revolutionized the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Inhibiting the activity of BTK blocks signaling through the B-cell receptor (BCR), a key pathway that sends pro-survival messages to CLL cells. Currently, there are two types of BTKi approved for the treatment of CLL / SLL. Covalent BTKi (ibrutinib, acalabrutinib, zanubrutinib) bind to BTK irreversibly, and noncovalent BTKi (pirtobrutinib) bind to BTK reversibly.
Because both types of BTKi are given continuously until disease progression or intolerable side effects develop, over the long term, patients can develop resistance mutations. Patients on covalent BTKi tend to develop mutations at the C481S site on BTK, while patients on noncovalent BTKi tend to develop mutations at the T474I and L528W sites on BTK. Rocbrutinib (formerly LP-168) is a dual BTK inhibitor that can bind to wild-type BTK irreversibly and C481-mutated BTK reversibly, and it is currently being tested in clinical trials.
Methods and Participants:
This was a preclinical study, which ran several different tests using isolated proteins, cells in a dish, or mouse models.
Results:
- Rocbrutinib binds to the wild-type, C481S, T474I, and L528W forms of BTK.
- In a lymphoma cell line that had been genetically modified to only express C481S, T474I, or L528W forms of BTK, rocbrutinib inhibited activation of BTK as well as several other downstream proteins in the BCR signaling pathway, including PLCγ2, ERK, and AKT.
- In primary CLL B-cells, treatment with rocbrutinib reduced activation of BTK, PLCγ2, ERK, and AKT.
- This inhibition of BCR signaling was also observed in primary CLL B-cells with C481S-mutated BTK.
- In two different mouse models of CLL, rocbrutinib improved survival compared with ibrutinib.
Conclusions:
This study shows that rocbrutinib inhibits BTK and BCR pathway signaling even in the presence of common BTK mutations. This work on robrutinib’s mechanism of action complements phase 1 clinical trial data showing that 78% of patients with relapsed / refractory CLL who are treated with rocbrutinib respond to treatment. Inhibiting the BCR pathway continues to be a critical part of treating CLL.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Targeting BTKi-resistant CLL using the dual irreversible/reversible 4th generation BTK inhibitor rocbrutinib
