Fusing Non-Covalent and Covalent BTK Inhibitors for CLL with Rocbrutinib

Discover new research shared at the 2025 American Society of Hematology (ASH) meeting about rocbrutinib, a next-generation BTK inhibitor being studied for people living with chronic lymphocytic leukemia (CLL). 

Why new BTK inhibitors are still needed in CLL

BTK inhibitors are a key part of CLL care. They block Bruton’s tyrosine kinase (BTK), a protein that CLL cells need to survive. Over time, however, CLL can change and become resistant to these treatments.

Some resistance happens because of changes, called mutations, in the BTK protein itself. Newer non-covalent BTK inhibitors like pirtobrutinib (Jaypirca, Eli Lilly) can help overcome resistance, but only temporarily. People who have already received both a BTK inhibitor and a BCL-2 inhibitor, such as venetoclax (Venclexta, AbbVie), can have limited options. This is why doctors continue to work on developing new treatments. 

What makes rocbrutinib different

Rocbrutinib, also called LP-168, is designed to combine two ways of blocking BTK. It is both a covalent and non-covalent BTK inhibitor. This means it binds both permanently to the BTK protein and temporarily with hydrogen and ionic bonds. Doing so helps it overcome common resistance mutations. This dual action is meant to help rocbrutinib keep working even when CLL has learned how to bypass earlier BTK inhibitors. 

Who was included in the phase 1 study

This phase 1 study enrolled 42 people with relapsed or refractory CLL who had already received at least one BTK inhibitor. Seventeen of the participants had also been treated with a BCL-2 inhibitor. Many patients had high-risk features such as unmutated IGHV, del(17p)/TP53 mutations, or complex chromosome changes. Participants received rocbrutinib for a minimum of 12 cycles, about one year. 

How well rocbrutinib worked

Early results from the trial showed that patients needed to take rocbrutinib for a median of 22.4 months. Among people treated at the 200 mg and 300 mg daily doses, 78.3% of patients experienced a reduction in cancer cells following treatment. Patients were alive without CLL progressing for a median of 28.1 months since starting treatment. In people who had previously received both BTK inhibitors and a BCL-2 inhibitor, response rates were encouraging, especially at the 300 mg dose. 

Side effects seen in the study

Most side effects were mild to moderate. Common side effects included infections, low blood counts, diarrhea, cough, headache, joint aches, and constipation, among others. Atrial fibrillation, which can be a concern with some BTK inhibitors, was uncommon in this study. To learn how side effects from CLL treatments are managed, click here. 

What this means moving forward

Rocbrutinib is a promising new BTK inhibitor designed to overcome common resistance changes in CLL. In an early study of heavily pretreated patients with high-risk types of CLL, many people responded to treatment, and side effects were manageable. This may give patients with limited options another treatment to help them. Ongoing research will help clarify who may benefit most from this approach and how it fits into future CLL care. 

If you’d like to receive rocbrutinib, click the button below to see if you’re eligible to join this clinical trial. To learn how clinical trials work in general, click here. 

Check Your Eligibility to Receive Rocbrutinib

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Source: 

• Updates of R/R CLL with prior exposure to Bruton’s tyrosine kinase (BTK) inhibitor and/or bcl-2 inhibitor in the Phase 1 trial of LP-168 (Rocbrutinib), a novel COVALENT and non-COVALENT BTK inhibitor