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Next Therapies After Noncovalent BTK Inhibitors

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Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, MDCM (retired), MSEd

The Bottom Line:

Venetoclax produced high response rates in patients with CLL who had previously been treated with a noncovalent BTK inhibitor.

Who Performed the Research and Where Was it Presented:

Dr. Meghan Thompson from Memorial Sloan Kettering Cancer Center and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting 2024.

Background:

As more and more drugs have become available to treat chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), doctors and patients alike want to know what is the best way to sequence these therapies. Noncovalent BTK inhibitors (ncBTKi) are a relatively new class of drugs that are similar to covalent BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib), but they bind to BTK in a reversible manner. Some experts argue that BTK should continue to be inhibited as long as it successfully controls CLL / SLL. Using a drug that binds differently and, therefore, can overcome some of the most common reasons for resistance to the covalent BTKi has become a helpful new option, but does this lead to problems when patients eventually relapse on the ncBTKi? As with nearly all therapies, ncBTK inhibitors are not curative, so most patients eventually relapse. The question is what comes next after treatment with a ncBTKi, and how well will it work?

The FDA has approved the ncBTKi pirtobrutinib, and other ncBTKi, such as nemtabrutinib, are still being tested in clinical trials.

Methods and Participants:

This multicenter retrospective study used data from patients with CLL or Richter transformation who had been treated with and discontinued an ncBTKi for any reason. Data were collected on up to 2 lines of therapy after ncBTKi discontinuation.

Results:

  • Researchers identified 124 patients with CLL who were treated with and discontinued a ncBTKi.
  • Patients had received a median of 4 treatments prior to ncBTKi.
  • The median duration of ncBTKi treatment was 11 months, with an overall response rate of 56%.
  • Most patients (75%) discontinued ncBTKi due to progressive disease, while 12% discontinued it due to side effects.
  • After treatment with ncBTKi, 92 CLL patients received another line of therapy.
  • Overall, the median progression-free survival for the next line of therapy after ncBTKi was 15 months.
  • The overall response rate was high (72%) for patients who went from ncBTKi to a venetoclax-based treatment and was even higher (89%) in patients who had not previously been treated with venetoclax.
  • The median progression-free survival for venetoclax treated patients was 23 months in venetoclax naïve patients and 8 months in previously venetoclax-exposed patients.
  • For patients with Richter transformation (N=32), the median duration of ncBTKi treatment was 3 months, and the overall response rate was 31%.
  • Among the 25 patients who received another line of therapy after ncBTKi, the median progression-free survival was 2 months.

Conclusions:

In patients with CLL who had previously discontinued a ncBTKi, venetoclax-based therapies produced a reassuringly high overall response rate. Progression-free survival on venetoclax was nearly two years in patients who had not previously been treated with venetoclax but only 8 months in previously venetoclax-exposed patients. Knowing that venetoclax works better in unexposed patients raises the question of whether it makes the most sense for patients to try an ncBTKi before venetoclax after progressing on a cBTKi. We don’t know, and with more choices, we have more complex sequencing options to consider.

The bottom line is that it is great to see that there are effective options for treatment after ncBTKi, but it is still important to consider the next lines of therapy. While these therapies can buy more time for patients, none of the current treatments are curative, so researchers have more work to do.

Links and Resources:

Watch the interview on the abstract here:

Next Therapies After Noncovalent BTK Inhibitors – Dr. Meghan Thompson

You can read the actual ASH abstract here: Outcomes of Therapies Following Discontinuation of Noncovalent Bruton’s Tyrosine Kinase Inhibitors for Patients with Chronic Lymphocytic Leukemia and Richter Transformation: Results from an International, Multicenter Study