Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, MDCM (retired), MSEd
The Bottom Line:
Initial phase 1 clinical trial results show that BTK degrader NX-5948 produces rapid clinical responses in patients with relapsed / refractory CLL.
Who Performed the Research and Where Was it Presented:
Dr. Nirav Shah and colleagues from the Medical College of Wisconsin presented the results at the American Society for Hematology (ASH) Annual Meeting 2024.
Background:
Several new drugs have been approved for treating chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL) in the past decade, and patient outcomes have improved substantially. Nowadays, most patients will receive a covalent irreversible Bruton tyrosine kinase inhibitor (cBTKi: ibrutinib, acalabrutinib, zanubrutinib) or the noncovalent reversible BTK pirtobrutinib. And/or a BCL2 inhibitor (BCL2i: venetoclax) as part of their treatment course. While these therapies provide durable remissions, they are not curative, and some patients relapse after receiving both of these therapies. Patients who are double refractory to both BTKi and BCL2i currently have limited options.
BTK degraders are an experimental new option for double-refractory patients. They work by tagging the BTK enzyme for destruction by the proteasome, which acts as the cell’s garbage disposal. Because the whole enzyme is destroyed, BTK degraders are effective regardless of whether patients have resistance mutations to covalent or noncovalent BTKi. Several BTK degraders, including NX-5948, are being tested in clinical trials.
Methods and Participants:
This phase 1 clinical trial tested the BTK degrader NX-5948 in patients with relapsed / refractory B-cell cancers, including CLL / SLL. Eligible patients had received 2 or more prior lines of therapy.
Results:
- 87 patients have enrolled in the trial, including 34 patients with CLL / SLL.
- Patients had received a median of four prior lines of therapy.
- 97% of patients had previously been treated with a BTKi, and 88% had been treated with both a BTKi and a BCL2i.
- The overall response rate was 76%. Most responses occurred within the first 8 weeks, and responses deepened over time.
- Responses were seen in difficult-to-treat patients, including some with:
- Central nervous system (CNS) involvement
- Double refractory CLL to both BTKi and BCL2
- Prior pirtobrutinib exposure
- TP53 mutations
- BTK mutations including the common cBTKi resistance mutation C481S and ncBTKi resistance mutations L528W, T474I and V416L/M.
- PLCG2 mutations
- The most common moderate to severe side effect was low neutrophil counts (15%).
- Overall, the most common side effects were bruising (44%), low platelet counts (24%), small purple-brown spots on the skin (29%), fatigue 21%), low neutrophil counts (18%), rash (24%), and headache (24%).
- No new atrial fibrillation (abnormal heart rhythm) or high blood pressure cases were observed.
Conclusions:
Initial results from this phase 1 clinical trial show that BTK degrader NX-5948 produces rapid clinical responses in patients with relapsed / refractory CLL, including many difficult-to-treat patients with few options. Thus far, it also appears to be well-tolerated. Moving forward, researchers are looking to further define the safety of NX-5948, determine the best dose to give patients and use NX-5948 as a third line of therapy for patients who have developed resistance mutations to BTKi and BCL2i.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Efficacy and Safety of the Bruton’s Tyrosine Kinase (BTK) Degrader NX-5948 in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL): Updated Results from an Ongoing Phase 1a/b Study
