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Phase 1 Study of BTK Degrader BGB-16673 for B-Cell Cancers

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Medically reviewed by Dr. Brian Koffman

The Bottom Line:

Though it is still very early on, BTK degrader BGB-16673 appears tolerable. Clinical trials of BTK degraders may be especially of interest to CLL patients who have developed resistance to BTK inhibitors.

Who Performed the Research and Where Was it Presented:

Dr. Meghan Thompson from Memorial Sloan Kettering Cancer Center and colleagues presented the study design at the American Society for Hematology (ASH) Annual Meeting 2023.

Background:

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) cells depend on Bruton tyrosine kinase (BTK), a key enzyme in the B-cell receptor pathway, for survival. BTK inhibitors such as ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib bind to BTK and shut it off, which has been incredibly effective for treating CLL. However, BTK inhibitors must be taken continuously, and resistance mutations can develop over time. Thus, new strategies are needed for targeting BTK and the B-cell receptor pathway. BTK degraders destroy the BTK protein rather than bind to it like BTK inhibitors. Several BTK degraders are being tested in clinical trials, including BGB-16673.

Methods and Participants:

This is an ongoing phase 1 clinical trial testing the safety of BGB-16673 in humans for the first time.

  • The trial is open to patients with relapsed / refractory CLL, Waldenström macroglobulinemia, mantle cell lymphoma, marginal zone lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, or Richter transformation.
  • If approved for their disease, patients must have been treated with 2 or more prior therapies, including a covalent BTK inhibitor.
  • The trial’s objective is to evaluate safety and tolerability and determine the recommended dose level.

Results

  • As of May 2023, 26 patients had been enrolled, including 10 patients with CLL.
  • The median number of prior therapies was 3.5, including covalent BTK inhibitors, noncovalent BTK inhibitors, and BCL2 inhibitors.
  • The most common side effects were bruising (31%), fever (23%), low white blood cell counts (23%), and increased levels of lipase, an enzyme that breaks down fats (23%).
  • No patients discontinued treatment due to adverse events, but two patients had dose reductions because of adverse events.
  • One patient died from sepsis.
  • Preliminary data show deep, sustained reductions in BTK protein levels in peripheral blood and tumor tissue.

Conclusion:

It is still very early in this ongoing study, but thus far, BGB-16673 appears to be tolerable. Clinical trials of BTK degraders may be especially of interest for CLL patients who have developed resistance to BTK inhibitors and relapsed. If you are interested in participating in this clinical trial, more information can be found here: A Dose-Escalation and Expansion Study of BGB-16673 in Participants With B-Cell Malignancies.

It’s good news that these new ways to target BTK are being developed to extend the time those with CLL / SLL can benefit from turning off that pro-survival pathway.

Links and Resources:

Watch the interview on the abstract here:

BGB-16673 BTK Protein Degrader for Relapsed CLL and B-Cell Cancers – Dr. Meghan Thompson ASH 2023

You can read the actual ASH abstract here: First Results from a Phase 1, First-in-Human Study of the Bruton’s Tyrosine Kinase (BTK) Degrader Bgb-16673 in Patients (Pts) with Relapsed or Refractory (R/R) B-Cell Malignancies (BGB-16673-101)

Take care of yourself first.

Ann Liu, PhD