Authored by Brian Koffman, MDCM (retired), MSEd
Bottom Line:
The BTK degrader BGB-16673 shows promise in relapsed / refractory CLL / SLL patients. By degrading or destroying BTK instead of blocking it, degraders may overcome resistance.
Who Performed the Research and Where Was it Presented:
Dr. Meghan Thompson of Memorial Sloan Kettering Cancer Center, New York, NY, and colleagues presented the results during an oral session at the American Society for Hematology (ASH) Annual Meeting 2024.
Background:
Chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL) cells have increased dependence on their B-cell receptors (BCR) signaling. Blocking BTK with BTK inhibitors (BTKi), namely ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib, blocks BCR signaling and has markedly improved overall and progression-free survival for patients. Still, resistance eventually develops in nearly all patients. Most resistance is due to mutations in BTK that prevent the inhibitors from binding, thus inhibiting the BTK enzyme. BTK degraders block the BTK pathway in an entirely different way. They are larger molecules that attach to BTK at one end and at the other end to E3 ligase, which marks BTK for destruction by proteosomes, the cell’s protein recyclers. The BTK isn’t inhibited; it’s chewed up. For more background on the difference between BTK inhibitors and degraders, read CLL Society’s article: BTK Inhibitors in Chronic Lymphocytic Leukemia.
Results:
Study Population:
- 49 patients with CLL were enrolled and treated.
- The median age was 70 years.
- The average number of prior therapies was four, including prior covalently binding BTKi (ibrutinib, acalabrutinib, zanubrutinib) in 92%, BCL2 inhibitors such as venetoclax in 86%, and noncovalent BTK inhibitors (pirtobrutinib) in one in four. This group was very tough to treat, and they were running out of options.
- Most patients had high-risk prognostic markers, with 63% of those tested having del(17p) and/or TP53 mutation and 82% having unmutated IGHV.
- The median follow-up was almost 8 months.
Side Effects:
- Ninety-six percent of patients reported some side effects, including:
- fatigue in 35%
- contusion in 29%
- diarrhea in 27%
- The most common, more severe (grade ≥3) adverse events were low neutrophil counts (neutropenia) in 20% and pneumonia in 10%.
- No atrial fibrillation was observed.
- One patient had a severely raised rash that required a dose reduction.
- Three patients died. The causes of death were:
- septic shock
- bronchopulmonary aspergillosis/cerebral aspergillosis (this is a fungal infection in the lung and brain seen in the immunocompromised)
- pneumonia in the context of disease progression
Responses:
- In the 49 for which we have results, the overall response rate (ORR) was 78% (38/49), and the complete response (CR) was 4% (n=2).
- At the 200 mg dose, the ORR was 94% (15/16), including the 2 CRs.
- All 17 patients who are still on medication at nine months or longer are still responding.
- Responses were seen in all subsets of patients, including those with multiple prior therapies, including BTK inhibitors and venetoclax, and those with poor prognostic markers.
Conclusions:
This is very early and very encouraging data. We know very little about the durability of the results, which is what patients care most about. Will this medication help CLL / SLL patients live longer? We don’t know yet. The three deaths and some of the other complications, such as pneumonia, seen in one in ten could be related to the immunocompromised state of the patients being studied. Most patients had advanced disease and multiple prior therapies. We don’t know if BGB-16673 increased their already high infection risk. Future research should sort this out.
In a high-risk, heavily treated group of patients running out of options, seeing 15 out of 16 respond at the higher dose of 200 mg and a couple of complete remissions indeed suggests this a potent therapy. We expect to see more reports with longer follow-ups and bigger trials as BGB-16673 progresses in its development. Other interesting BTK degraders are also being developed, including NX-2127 and NX-5498. Hopefully, these drugs will be important options for CLL / SLL patients in the not-too-distant future.
Links and Resources:
Watch the interview on the abstract here:
To read the actual ASH abstract that has many details about the trial and the results, click on Preliminary Efficacy and Safety of the Bruton Tyrosine Kinase Degrader BGB-16673 in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Results from the Phase 1 CaDAnCe-101 Study.
