This video features Professor Constantine Tam, MBBS, MD. Dr. Tam is the Director of Haematology and leads the Chronic Lymphocytic Leukemia (CLL) Program at Peter MacCallum Cancer Centre located in Melbourne, Australia. Dr. Tam gave two oral presentations addressing two separate ongoing trials of the third–generation Bruton’s Tyrosine Kinase inhibitor (BTKi) zanubrutinib (Brukinsa®). This video was recorded in 2019 at the 61st Annual Meeting of the American Society of Hematology in Orlando, FL.
The first targeted therapy commercially available for the treatment of chronic lymphocytic leukemia (CLL) and small lymphatic lymphoma (SLL) was ibrutinib (Imbruvica®), and is considered to be a first generation BTKi. The side effects associated with ibrutinib occur because it not only acts on Bruton’s Tyrosine Kinase (BTK), but also inhibits several other proteins found on CLL cells. The second BTKi drug to be approved for CLL was acalabrutinib (Calquence®), which appears to have fewer side effects than ibrutinib. As of yet, there has not been a head-to–head comparison study between these two drugs. But clinical reports from CLL providers indicate fewer adverse effects. Zanubrutinib is a third generation BTKi, and is currently only approved commercially for relapsed or refractory Mantle Cell Lymphoma (MCL). This pattern of approval (first for MCL then eventually CLL) has occurred with the other BTKi drugs that have been approved in the past. These three agents can all potentially cause CLL cells to become resistant to the BTK blockade because they are covalently bound to the BTK protein. For new information on fourth generation BTKi drugs undergoing clinical trials that appear to overcome this resistance mechanism, click here.
In this video, Dr. Tam (who is the lead investigator of the Sequoia trial) discusses the most recent results of these trials: Efficacy and Safety of Zanubrutinib in Patients with Treatment-Naive Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) with Del(17p): Initial Results from Arm C of the Sequoia (BGB-3111-304) Trial and Treatment with the Bruton Tyrosine Kinase Inhibitor Zanubrutinib (BGB-3111) Demonstrates High Overall Response Rate and Durable Responses in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Updated Results from a Phase 1/2 Trial
Arm C of the Sequoia trial examined 109 treatment-naive patients whose CLL is characterized by the 17P deletion, which is a mutation of the TP53 gene. In this update, the overall response rate (ORR) was 92.7%, with a median follow-up of 10.0 months. Of this group, two patients had a complete response (CR; 1.9%), 86 patients had a partial response (PR; 78.9), and 13 patients had a partial response with only lymphocytosis (elevated lymphocytes in the blood). The most common adverse event (AE) was neutropenia (10.1%), which is a reduction in the white blood cell count known as neutrophils. Other AEs included pneumonia (3.7%) and hypertension (2.8%).
AU-003 was the first study of zanabrutinib in humans. This clinical trial provides the most extended follow-up data on zanabrutinib, at more than 30 months. Furthermore, AU-003 enrolled 384 patients, of which 123 had CLL/SLL. There were 22 CLL patients for whom this was the first treatment (also known as treatment naïve), and 101 who had relapsed after at least one other therapy. The responses in the treatment naïve group included five with complete response (22.7%), and 17 had partial response (77.3%). The ORR for these 22 patients was 100%. None of the five CRs were among patients with deletion 17P. In the second group of relapsed or refractory (R/R) patients, the ORR was 92.3%, with 14 CR (13.9%), 73 PR (72.3%), and 8 PR with lymphocytosis. The discontinuation rate as a result of AEs was 4.1%. The most common AEs in this trial included contusions (bruising 47.2%), upper respiratory infections (42.3%), diarrhea (31.7%), cough (29.3%), headache (23.6%), and fatigue (20.3%). Grade ≥3 atrial fibrillation occurred in 1.6% of patients.
Zanubrutinib appears to be equally efficacious to the already approved BTK inhibitor agents ibrutinib and acalabrutinib, and seems to have a better side effect profile. However, the only way to accurately compare all the different agents is by performing a randomized controlled trial (RCT). In a RCT these agents would be evaluated under the same conditions and criteria, but would allow researchers to determine actual differences in efficacy and adverse events.
What we would expect based on historical approvals of the other BTK inhibitors is that zanubrutinib will likely be indicated for CLL sometime in the next year or two.
Ibrutinib was a real breakthrough in the treatment of CLL. However, approximately 20 percent of patients cannot tolerate this medication and need to eventually discontinue. The availability of newer agents with what appears to be fewer side effects may provide an option for that 20 percent who cannot tolerate ibrutinib, or to a lesser extent acalabrutinib.
Having more agents available for physicians to choose from to treat CLL is a good thing, because it allows physicians to tailor the medication regimen to the patient’s needs, preferences, and tolerances.
More information is available on the AU-003 trial at https://clinicaltrials.gov/ct2/show/NCT02343120. The Sequoia Trial information is available at https://clinicaltrials.gov/ct2/show/NCT03336333. For more information on clinical trials in general, visit the CLL Society Website.
Thanks for reading this summary and watching this interview.
Stay strong; we are all in this together!
Thomas. E. Henry III, MBA, RPh, CPh