CLL Research: Zanubrutinib - A Second-Generation BTK Inhibitor - Arm C SEQUOIA Study Update

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CLL Research: Zanubrutinib - A Second Generation BTK Inhibitor in Treatment-Naïve CLL/SLL Patients with deletion (17p) - Poster Presentation at ASH 2020

Zanubrutinib is a second-generation BTK inhibitor. BTK inhibitors disable the protein Bruton’s Tyrosine Kinase that plays a major role in the rapid proliferation of CLL/SLLcells. By blocking this protein, BTK inhibitors slow the rapid proliferation of malignant cells and bring the disease under control.

During the 62nd Annual Meeting and Exposition of the American Society of Hematology (ASH2020), Dr. Jennifer R. Brown, M.D., Ph.D., the head of the Chronic Lymphocytic Leukemia (CLL) program at the Dana-Farber Cancer Institute, in Boston, gave an oral poster presentation entitled: Efficacy and Safety of Zanubrutinib in Patients with Treatment-Naïve Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) with del(17p): Follow-up Results from Arm C of the SEQUOIA (BGB-3111-304) Trial.

 

Background: Zanubrutinib – A Second-Generation BTK Inhibitor

Zanubrutinib is a second-generation BTK inhibitor designed to maximize BTK occupancy and to minimize off-target inhibition of the TEC (produced by the TEC gene) and EGFR (Epidural Growth Factor Receptor) families of kinases (enzymes). Many of the adverse effects of ibrutinib (Imbruvica®) and acalabrutinib (Calquence®) result from these drugs’ affinity to kinases other than BTK. In the ASPEN study of patients with Waldenström macroglobulinemia {a type of non-Hodgkin’s lymphoma (NHL) where cancer cells make large amounts of an abnormal protein called macroglobulin}, zanabrutinib displayed safety advantages compared with ibrutinib. In particular, zanabrutinib patients experienced reduced atrial fibrillation (AF) [an irregular and often rapid heart rate that occurs when the two upper chambers of your heart experience chaotic electrical signals] rates compared with the group treated with ibrutinib. Two percent of the zanabrutinib patients experienced AF compared to 15% in the ibrutinib group.

The U.S. FDA and China have approved Zanubrutinib (Brukinsa®) for relapsed or refractory Mantle Cell Lymphoma (MCL); however, a review is underway for use in CLL patients. For access to this drug in CLL, clinical trials are currently the only option.
Patients with CLL/SLL whose tumor exhibits the deletion of chromosome 17p13.1 [del (17p)] have an unfavorable prognosis characterized by a shorter time to treatment and reduced progression-free survival during treatments. I among the 6-8% of CLL patients who exhibit deletion (17p). I required treatment just seven months after diagnosis. I have, however, been on ibrutinib for almost five years without disease progression.

The image to the left is a graphical image of deletion (17p). Note the shortened arm on the red chromosome.

Patients with deletion (17p) respond poorly to standard chemoimmunotherapy (CIT) such as fludarabine, cyclophosphamide, and rituximab (FCR) or bendamustine and rituximab (BR). This poor response to CIT is a significant factor in the short overall survival time of 17p patients seen before targeted therapies became available. In the past, patients with deletion (17p) had a median survival of 36 months after diagnosis. In other words, if you had deletion (17p), you had a 50% of not living beyond three years.

 

I need to clarify that this is historical data and no longer the current prognosis due to the advances in treatment brought by targeted therapies!

The approved targeted therapies that target BTK (ibrutinib/acalabrutinib), as well as venetoclax (Venclexta®) that targets the BCL-2 (b-cell lymphoma 2) protein, have been shown to improve outcomes for patients with del (17p).

The initial results from Arm C of the SEQUOIA trial (BGB-3111-304) of zanubrutinib - a second-generation BTK inhibitor, evaluated a large cohort of treatment-naïve CLL/SLL patients with del (17p) were presented at ASH2019. The 2019 data reviewed efficacy and safety with a median follow-up of ten months. Dr. Brown’s presentation shows updated results with a median follow-up of 22-months.

Methods: SEQUOIA Study Arm C

The SEQUOIA trial is an open-label (everyone knows what you’re getting), global, multicenter Phase III study that includes a non-randomized cohort (Arm C) of treatment-naïve patients with deletion (17p). Patients in Arm C received zanubrutinib 160mg twice daily. Adult patients with CLL/SLL who met the iwCLL (International Workshop on CLL) criteria for treatment were eligible if 65 years of age or older or if they were ineligible for FCR. The use of long-term anticoagulation was permitted. Eligibility for Arm C required verifying del (17p) by fluorescence in situ hybridization (FISH) with a minimum of 7% aberrant nuclei present.
For CLL, each investigator evaluated response per modified iwCLL criteria. For SLL, investigators assessed patient responses using the Lugano criteria.

Results: SEQUOIA Study Arm C – Zanubrutinib a Second-Generation BTK Inhibitor

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As of 4/15/2020 (data cutoff), the median follow-up was 18.2 months (range 5.0-26.3). For the 109 patients enrolled in the study, 97 patients (89.0%) remained on treatment with zanabrutinib, a second-generation BTK inhibitor. The best overall response rate (ORR) was 94.5%. As expected, with monotherapy with BTK inhibitors, only 3.7% had a complete response (CR), 87.2% had a partial response (PR), 4.6% had stable disease (SD), and disease progression occurred in 0.9% of patients. The estimated 18-month values for progression-free survival (PFS), duration of response (DoR), and overall survival (OS) were 88.6%, 84.0%, and 95.1%, respectively.

 

AEs of interest when using “pooled-terminology” or broader definitions included: infections – 64.2%, bleeding – 47.7%, [with 5.5% grade 3 (serious)], headache – 8.3%, hypertension – 8.3%, myalgia (muscle pain) – 4.6%, secondary skin cancers – 9.2%, secondary non-skin cancers – 4.6%, and atrial fibrillation or flutter – 2.8%.
Adverse events (AEs) reported in 10% or more of patients included: contusion or bruising – 17.4%,upper respiratory tract infections – 19.3%, neutropenia or low neutrophil count – 17.4%, diarrhea – 16.5%, nausea – 14.7%, constipation – 13.8%, rash – 13.8%, back pain – 12.8%, cough – 11.9%, arthralgia or bone/joint pain – 11.0%, and fatigue – 10.1%.

Four patients (3.7%) discontinued zanabrutinib due to adverse events, and three patients died (two after disease progression and one after bloodstream infection that followed progression.) There were no sudden or unknown deaths among this cohort.

Conclusions: Zanubrutinib - A Second-Generation BTK Inhibitor

BeiGene, a Chinese biopharmaceutical company, developed zanubrutinib – a second-generation BTK inhibitor (as is acalabrutinib.) At this time, zanubrutinib is approved only for mantle cell lymphoma (MCL) in the U.S. (2019) and only available in clinical trials for the treatment of CLL. China has approved it for CLL. Ongoing clinical trials are underway in the U.S., U.K., Australia, New Zealand, Italy, and South Korea.
The data from the extended follow-up included in this report showed the durability of responses in this high-risk group [deletion (17p).]

Zanubrutinib was generally well tolerated with low rates of discontinuation due to adverse events. This report’s data support the potential utility of zanabrutinib, a second-generation BTK inhibitor, in the frontline management of a frontline disease.
Ongoing clinical trials include zanabrutinib as monotherapy or in combination with venetoclax and several monoclonal antibodies.

Third-generation BTK inhibitors such as LOXO-305 and ARQ-531 are also currently underway.

At this point, there have been no head-to-head studies of zanabrutinib with the currently available ibrutinib or acalabrutinib, which makes it impossible to compare the efficacy or safety of zanubrutinib directly. It will be interesting to see if the FDA approves this compound for CLL and its place in CLL treatment in the future.

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