Authored by Dr. Brian Koffman
Bottom Line:
Blocking the BTK pathway transformed treatment for chronic lymphocytic leukemia, but resistance can develop. Rather than inhibit BTK, the BTK degrader BGB-16673 destroys it with two-thirds of patients responding.
Who Performed the Research and Where Was it Presented:
Dr. Ricardo Parrondo led an international group of researchers. He presented the oral abstract of these encouraging first results on the last day of the 2024 European Hematology Association (EHA) Annual Meeting in Madrid.
Background:
Treatment for chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL / SLL) was revolutionized when it was understood that the cancer cells depended on their survival and proliferation on signaling through the B-cell receptor (BCR). Several medications have been developed to block this pathway, but the most impactful has been the BTK inhibitors, starting with ibrutinib, followed by acalabrutinib, zanubrutinib, and pirtobrutinib. These oral drugs have proven superior to all prior chemo-immunotherapies therapies (CIT) and have become one of the mainstays of care, prolonging lives and offering patients who were previously out of options new hope. However, CLL / SLL cells can eventually develop mutations that cause these medications to stop working. Finding new ways to block BTK when resistance develops would benefit patients.
BTK degraders, such as the experimental BGB-16673, work differently. While they are still “small molecules” that can be taken orally, they have a more complex structure. Instead of blocking the activity of BTK, an enzyme or kinase, they tag the whole molecule for destruction or degradation. BTK is completely broken down. Essentially, its component molecules are recycled and used to build new proteins in the cell. This destruction, of course, leads to a complete stop of the BCR signaling, which in turn leads to control of the CLL / SLL. Moreover, at least theoretically, resistance to other BTK blockers should not influence its efficacy.
Methods and Participants:
This was a Phase 1 trial to find the optimal dose and assess drug safety. Patients must have relapsed / refractory CLL / SLL with a minimum of 2 prior therapies. BGB-16673 was dosed once daily orally.
Results:
- Enrollees:
- 42 patients with CLL were enrolled.The median age was 70 years.39 were treated at the following doses: (50 mg [n=1]; 100 mg [n=5]; 200 mg, [n=15]; 350 mg, [n=14]; 500 mg, [n=4]).For treated patients, the median number of prior therapies was 4 (range, 2-8), including covalent or cBTKis (n=37; 95%), BCL2 inhibitors such as venetoclax (n=34; 87%), and noncovalent BTK inhibitors such as pirtobrutinib (ncBTKis; n=10; 26%). Overall, it is a tough group to treat.Of the patients who were tested, 54% (20/37) had del(17p) and/or TP53 mutation, 87% (27/31) had unmutated IGHV, and 43% (12/28) had a complex karyotype, all bad prognostic markers.
- The median follow-up time was only 3.3 months, so these are very early results
- Adverse Events and Dose Tolerance:
- Maximum tolerated dose was not reached
- The most common side effects were contusion (31%; all mild), fatigue (31%; all mild), diarrhea (26%; all mild), and low neutrophil count (23% total with 18% more severe or grade 3).
- One patient had a treatment-emergent adverse event or TEAE consisting of grade 3 or severe hypertension.
- No atrial fibrillation was observed.
- Two patients had TEAEs that were fatal (septic shock and pneumonia); neither was considered related to treatment.
- Two additional patients had TEAEs that led to treatment discontinuation (subdural or brain hemorrhage and thyroid cancer).
- One patient had a dose reduction due to grade 2 or moderate and not dangerous arthralgia or joint pain.
- Responses:
- Thirty-five of 39 patients (90%) remain on therapy (4 discontinuations: one due to progressive disease and the other three due to adverse events).
- The overall response rate for the 24 patients whose responses could be assessed during a data cut-off for this abstract was 67%, with all but one patient still responding. Responses were seen at the lowest dose in patients previously treated with a cBTKi (n=16) and a ncBTKi (n=2) and in patients with and without BTK mutation.
Discussion and Conclusion:
BGB-16673 is producing impressive early results in difficult-to-treat patients running out of options. It worked at low doses and in patients resistant to irreversible (ibrutinib, acalabrutinib, zanubrutinib) and reversible (pirtobrutinib) BTK inhibitors. Though the numbers are small, the lack of atrial fibrillation is encouraging, as was the fact that 90% of patients remained on therapy. The durability of response is yet to be assessed, though the first few enrollees are now more than a year out and are doing well. Degraders are a promising part of the future for CLL / SLL treatment. Not surprisingly, several other BTK degraders are in development, and CLL Society will be presenting more results on the different drugs.
Links and Resources:
Listen to my monologue below.
Read the abstract at: PRELIMINARY EFFICACY AND SAFETY OF THE BRUTON TYROSINE KINASE (BTK) DEGRADER BGB-16673 IN PATIENTS WITH RELAPSED OR REFRACTORY (R/R) CLL / SLL: RESULTS FROM THE PHASE 1 BGB-16673-101 STUDY
Stay strong. We are all in this together.
Brian Koffman MDCM (retired) MS Ed (he, him, his)
Co-founder, Executive VP and Chief Medical Officer
CLL Society, Inc.
