Oncology

Chronic Lymphocytic Leukemia

Advertisment

Newer Covalent BTK Inhibitors: From Bench to Bedside

clinical topic updates by Kerry A. Rogers, MD
Overview

Newer covalent BTK inhibitors acalabrutinib and zanubrutinib offer safety improvements over ibrutinib for patients with chronic lymphocytic leukemia (CLL). Clinical trial and real-world data provide important insights into the use of these therapies in this treatment setting.

 

Expert Commentary
“It is extremely important to note that all 3 of the covalent BTK inhibitors inhibit BTK in very similar ways, so we do not expect the other 2 drugs to work if a patient's disease has become resistant to 1 of them. However, the newer agents do have better tolerability. Thus, for patients who have developed intolerance to ibrutinib, switching to acalabrutinib or zanubrutinib is a good strategy.”
— Kerry A. Rogers, MD

Of the 3 US Food and Drug Administration (FDA)–approved covalent BTK inhibitors, acalabrutinib and zanubrutinib are newer covalent agents, and ibrutinib is an older covalent agent. When these newer drugs were being developed preclinically, they were purposely moved forward in development because they were more selective, with fewer off-target effects. We suspect that this is what drives the reduction in adverse events that is seen with acalabrutinib and zanubrutinib.

 

It is a little unclear which next-generation BTK inhibitor should be preferred in patients with CLL. Most guidelines—and, really, the evidence—support the utilization of either acalabrutinib or zanubrutinib over ibrutinib due to the improved cardiovascular safety. In the relapsed/refractory setting, head-to-head trials in CLL with ibrutinib show that acalabrutinib has lower rates of hypertension and atrial fibrillation and zanubrutinib has lower rates of atrial fibrillation compared with ibrutinib. Although there are, of course, some other differences in the side-effect profiles, both acalabrutinib and zanubrutinib are preferred over ibrutinib specifically because of the safety differences.

 

Between acalabrutinib and zanubrutinib, it is difficult to say which is better for an individual patient with CLL. Acalabrutinib has a twice-daily dosing schedule, and there is an option for daily dosing with zanubrutinib, making the decision easy for the small number of patients who are unable to take pills twice per day. There are a few other differences, such as a higher rate of headaches with acalabrutinib and a lower incidence of hypertension compared with ibrutinib, so the decision can be patient specific, depending on an individual’s concerns and health history.

 

Anytime you have a drug that is used in the real world, it is always interesting to see how that agent differs between the real-world population and the clinical trial population. Usually, we see higher rates of treatment discontinuation due to adverse events as a wider variety of patients are exposed. Typically, the first patients to get drugs in clinical trials are those who have experienced a lot of other treatments and have a high motivation to remain on treatment. I think that this drives the higher discontinuation rates that are observed in real-world studies. I look forward to seeing additional real-world data on the newer covalent BTK inhibitors and their use increase.

 

It is extremely important to note that all 3 of the covalent BTK inhibitors inhibit BTK in very similar ways, so we do not expect the other 2 drugs to work if a patient’s disease has become resistant to 1 of them. However, the newer agents do have better tolerability. Thus, for patients who have developed intolerance to ibrutinib, switching to acalabrutinib or zanubrutinib is a good strategy. In fact, in 2 studies examining switching to acalabrutinib in people who discontinued ibrutinib due to side effects, acalabrutinib was effective and had lower discontinuation rates. A similar study of zanubrutinib was conducted in CLL and other B-cell cancers.

References

Awan FT, Schuh A, Brown JR, et al. Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Blood Adv. 2019;3(9):1553-1562. doi:10.1182/bloodadvances.2018030007

 

Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388(4):319-332. doi:10.1056/NEJMoa2211582

 

Hillmen P, Brown JR, Eichhorst BF, et al. ALPINE: zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic leukemia. Future Oncol. 2020;16(10):517-523. doi:10.2217/fon-2019-0844

 

Huntington SF, de Nigris E, Puckett J, et al. Ibrutinib discontinuation and associated factors in a real-world national sample of elderly Medicare beneficiaries with chronic lymphocytic leukemia. Leuk Lymphoma. 2023;64(14):2286-2295. doi:10.1080/10428194.2023.2256911

 

Rogers KA, Thompson PA, Allan JN, et al. Phase II study of acalabrutinib in ibrutinib-intolerant patients with relapsed/refractory chronic lymphocytic leukemia. Haematologica. 2021;106(9):2364-2373. doi:10.3324/haematol.2020.272500

 

Seymour JF, Byrd JC, Ghia P, et al. Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial. Blood. 2023;142(8):687-699. doi:10.1182/blood.2022018818

 

Shadman M, Brown JR, Williams R, et al. Efficacy of zanubrutinib versus acalabrutinib in the treatment of relapsed or refractory chronic lymphocytic leukemia (R/R CLL): a matching-adjusted indirect comparison (MAIC). Presented at: 28th Annual International Congress on Hematologic Malignancies; February 29-March 3, 2024; Miami Beach, FL.

 

Shadman M, Flinn IW, Levy MY. Zanubrutinib in patients with previously treated B-cell malignancies intolerant of previous Bruton tyrosine kinase inhibitors in the USA: a phase 2, open-label, single-arm study. Lancet Haematol. 2023;10(1):e35-e45. doi:10.1016/S2352-3026(22)00320-9

 

Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib ± obinutuzumab vs obinutuzumab + chlorambucil in treatment-naive chronic lymphocytic leukemia: 6-year follow-up of ELEVATE-TN [abstract 636]. Abstract presented at 65th American Society of Hematology Annual Meeting and Exposition; December 9-12, 2023; San Diego, CA.

Kerry A. Rogers, MD

    Associate Professor With Tenure
    Division of Hematology
    Department of Internal Medicine
    The Ohio State University
    Columbus, OH
Advertisment