Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, MDCM (retired), MSEd
The Bottom Line:
Though it is still early on, ibrutinib appears to be effective in CLL patients with prior BTKi resistance mutations and is generally well-tolerated.
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 2024.
Background:
Bruton tyrosine kinase inhibitors (BTKi) have revolutionized the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). However, one of the challenges with Bruton tyrosine kinase inhibitors (BTKi) is that they have to be taken continuously, and because of this, patients can develop resistance mutations over time. The most common mutation seen with covalent BTKi (ibrutinib, acalabrunitib, zanubrutinib) is at C481S, the binding site for covalent BTKi. With noncovalent BTKi (pirtobrutinib), mutations can develop at different sites, including T747I. Rocbrutinib (formerly LP-168) is a next-generation BTKi that works both covalently and noncovalently. It is capable of binding wild-type BTK, BTK with C481 mutations, and BTK with other non-C481 mutations.
Methods and Participants:
This was a phase 1 clinical trial of rocbrutinib in patients with relapsed / refractory B-cell cancers, including CLL. This was a dose escalation study, so patients received doses between 150 and 300 mg.
Results:
- Fifty patients have enrolled in the trial, and 47 have CLL.
- All patients had previously been treated with covalent BTKi; some had also been previously treated with noncovalent BTKi.
- 69% of patients with CLL remained progression-free at 18 months, and among patients who started at higher dose levels (≥200 mg), 77% were progression-free at 18 months.
- Among patients with mutations at key BTKi binding sites, the overall response rate was 78%.
- Common side effects (occurring in >20% of patients) included nausea, constipation, headache, abdominal pain, cough, diarrhea, dizziness, and fatigue.
- Some cases of infection and bruising (common BTKi side effects) were observed, but no cases of atrial fibrillation or hypertension were reported.
Conclusions:
Though it is still early on, rocbrutinib appears to be effective in CLL patients with prior BTKi resistance mutations and is generally well-tolerated. Larger efficacy trials are still in the works, but thus far, the early results are promising. Dual covalent and noncovalent inhibitors like rocbrutinib would give patients with CLL one more option for inhibiting BTK and extending the benefits of BTK inhibition. This type of drug could potentially be used after covalent and maybe even after noncovalent BTKi, but before a BTK degrader. How they will best fit into treatment sequencing is a long way from being determined at this very early but encouraging stage of their development.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: LP-168 (Rocbrutinib), a Novel Covalent and Non-Covalent Next-Generation Inhibitor of Bruton’s Tyrosine Kinase: Updates on the Phase 1 Trial and Initial Results of the CLL Gatekeeper Mutation Cohort
