The development of targeted therapies, including BTK inhibitors, for the treatment of B-cell malignancies has become an important therapeutic strategy for several diseases. Zanubrutinib is a covalent BTK inhibitor with selective and sustained inhibition of BTK. The development of Zanubrutinib was based on the concept of having minimal off-target kinase inhibition while achieving near complete BTK target occupancy to continuously suppress BCR signaling.
The translation of clinical trial data to clinical practice includes so much more than assessing the key end points of a study (e.g. overall survival, complete remission rate). Several key factors must be considered including the patient population studied, the specific disease(s) studied, prior treatment given, the presence of co-morbidities, a description of the concomitant medications that patients in the study were taking, the duration of treatment, and description of the study’s adverse events.
Understanding Clinical Evidence
BTK is a key signaling enzyme involved in the survival, proliferation, migration and interaction with tumor environment of B-cells. The irreversible covalent binding of Zanubrutinib to the Cys481 residue of BTK results in sustained inhibition of the kinase. Studies have reported BTK occupancy levels greater than 95% at trough concentrations of Zanubrutinib.
The pharmacology of Zanubrutinib, a potent BTK inhibitor, renders this drug suitable for investigation in a variety of B-cell malignancies. Clinical studies are underway in chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), Waldenström’s macroglobulinemia (WM), marginal zone lymphoma (MZL), and follicular lymphoma (FL).
Translating ALPINE Findings Into CLL/SLL Practice
The comparative Phase 3 ALPINE study evaluated Zanubrutinib vs Ibrutinib for the treatment of patients with relapsed or refractory CLL/SLL. The PFS and atrial fibrillation outcomes for Zanubrutinib were different from those observed with Ibrutinib.
These studies are important to the clinician for a number of reasons including the comparison of two different BTK inhibitors and their potential side effect profile, particularly with respect to atrial fibrillation and bleeding. The studies were conducted on specific populations with respect to their CLL/SLL disease and prior treatments. Therefore, these studies must be translated to the individual patient and their specific clinical situation. The patient’s disease status at time of consideration for BTK inhibitor therapy and prior treatment exposure(s) are key determinants to help the treating physician understand the expected treatment objective and potential treatment-related toxicity for a particular patient with a specific type and stage of B-cell malignancy.
Considering Long-Term Treatment
As treatment is given over a long period of time, consideration must be given to the long-term control of the patient’s disease and to the treatment’s side effect profile, with the patient able to continue the treatment in the long term.
Zanubrutinib was designed to provide prolonged plasma concentration above the potent inhibitory concentration that supports continuous BTK inhibition. Studies have evaluated BTK inhibition capability in peripheral blood and lymph node tumor tissues for Zanubrutinib compared to other drugs of the same class. In clinical practice, in addition to assessing the degree of tumor reduction, the physician will also have to consider any adverse events, treatment discontinuations or dose reductions, as well as the patient’s comorbid conditions and any concomitant medications.
Applying Evidence Across B-Cell Malignancies
The evidence for Zanubrutinib was gained in studies of a number of B-cell malignancies, including CLL/SLL, WM, MCL, MZL, and FL. Zanubrutinib was approved by the FDA for adult patients with CLL/SLL, WM, MCL (graded by FDA as accelerated approval for treatment of patients with MCL who have received at least one prior therapy and who have disease that is refractory to Rituximab and/or for whom Rituximab containing regimens declined to be used), MZL (graded by FDA as accelerated approval for treatment of patients with MZL who have received at least one prior anti-CD20 therapy), and FL (graded by FDA as accelerated approval for treatment of patients with FL and who have received two or more prior lines of systemic therapy for which rituximab therapy was used).
The indications for the use of Zanubrutinib to treat MCL, MZL, and FL are approved under the accelerated approval pathway for these diseases and responses are required to be assessed according to overall response rate and to have durations to establish the inferred clinical benefit(s).
Integrating Safety with Efficacy
BTK inhibitors are among the treatment options available for CLL/SLL along with chemo and immunotherapy. Evaluation of available treatment options may include consideration of both efficacy and safety data from clinical trials, as well as how these findings may apply in the real world.
Many factors must be taken into account when assessing a patient’s risk for cardiovascular complications, as well as their bleeding risk and risk of serious infection. Furthermore, the results of a patient’s laboratory tests, their previous treatment, and their current medications must also be considered. All these factors can have a significant impact on a patient’s treatment plan. When looking at the results from clinical trials it is also important to remember that participants in the trials are chosen based on specific criteria and thus may not necessarily be representative of everyone with the disease. Thus, results must be interpreted based on the individual patient’s clinical circumstances.
From Clinical Trials to Individualized Care
Clinical evidence and treatment comparison data contribute to the understanding of Zanubrutinib’s pharmacology. Ultimately, however, all clinical evidence must be integrated with clinical assessment of the individual patient.
However, translation of the Zanubrutinib clinical data to clinical practice must take into consideration a host of factors including the specific disease for which treatment is indicated, the patient’s disease status, prior therapy, treatment goals, comorbidities, concomitant medications, and the patient’s potential to tolerate a long-term treatment. Furthermore, current US labeling for Zanubrutinib should be consulted as approved indications, dosing, warnings and medication guides change over time.
While clinical trials form the basis for evidence-based oncology practice, the assessment of individual patients ultimately dictates how the findings from clinical trials can be applied to the care of individual patients.
Medical Disclaimer: The information provided in this article is intended for educational purposes only and should not be interpreted as medical advice, clinical guidelines, or a recommendation for any specific treatment.
