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ASH 2021: Dr. Constantine Tam on Novel BCL2 Inhibitor BGB-11417 For Patients with Relapsed/Refractory B-Cell Malignancies

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BCL2 is a protein that helps control whether a cell lives or dies by blocking a type of cell death called apoptosis. In chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), BCL2 is made in more significant amounts, which may keep cancer cells from dying. BCL2 inhibitors, such as venetoclax, bind to the BCL2 protein and block its action leading to cell death. Unfortunately, Venetoclax is so effective at rapidly killing cancer cells that it can lead to tumor lysis syndrome, a cluster of metabolic abnormalities resulting from the rapid, uncontrolled release of intracellular contents from cancer cells. Next-generation BCL2 inhibitors seek to reduce the risk of side effects such as tumor lysis syndrome.

At the American Society of Hematology (ASH) 2021, Dr. Alan Skarbnick, Director of the CLL program at Novant Health Cancer Institute in Charlotte, NC, interviewed Dr. Constantine Tam, a hematologist at the Peter McCallum Cancer Center in Melbourne, Australia. They discussed preliminary results from an ongoing phase 1 clinical trial studying the safety and efficacy of novel BCL2 inhibitor BGB-11417 alone and in combination with the next-generation BTK inhibitor zanubrutinib.

Takeaways:

  • BGB-11417 is a next-generation BCL2 inhibitor. It is about ten times more potent than venetoclax and is more specific for BCL2.
  • BGB-11417 also has a shorter half-life than venetoclax, which for patients means that the ramp-up period could potentially be shorter when starting treatment, though this is still to be tested.
  • This phase 1 study enrolled patients with relapsed/refractory Non-Hodgkin Lymphoma or CLL/SLL.
  • Thus far, 14 patients have been treated with BGB-11417 alone, and the side effects are what would be expected for this class of drugs.
  • Some common side effects included nausea (50%), diarrhea (21%), low white blood cell counts (21%), increases in liver enzymes (21%), dizziness (21%), and constipation (21%).
  • This trial is also testing the combination of BGB-11417 and zanubrutinib. Thus far, five patients have been treated with the combination, and it has been well-tolerated with no unexpected side effects.
  • Overall, five patients (all with Non-Hodgkin Lymphoma) discontinued treatment because of disease progression or lack of efficacy.
  • One patient with CLL developed tumor lysis syndrome and recovered with no additional complications.
  • Patients seem to be responding well, but it remains to be seen whether BGB-11417 will be better than venetoclax.

Conclusions:

Early-stage clinical trials are critical for determining the safety of new drugs. Though it is still early on, BGB-11417 appears tolerable at the tested dose levels. We look forward to seeing how the trial progresses. If the overall safety profile looks favorable, future head-to-head trials will be needed to see if BGB-11417 improves safety or efficacy over venetoclax.

Please enjoy this interview with Dr. Tam from the ASH meeting held in December 2021 in Atlanta, GA, virtually.

You can read the actual abstract here: Preliminary Safety and Efficacy Data from Patients (Pts) with Relapsed/Refractory (R/R) B-Cell Malignancies Treated with the Novel B-Cell Lymphoma 2 (BCL2) Inhibitor BGB-11417 in Monotherapy or in Combination with Zanubrutinib

Take care of yourself first.

Ann Liu, PhD