Zanubrutinib, a second-generation BTK inhibitor with superior efficacy and safety profile
- Kim Petiza
- Nov 27, 2024
- 5 min read
Updated: Feb 3
Zanubrutinib, marketed as Brukinsa, is a highly selective second-generation Bruton's tyrosine kinase (BTK) inhibitor developed to enhance efficacy and minimize off-target effects compared to first-generation inhibitors like ibrutinib. Its design aims to provide sustained BTK inhibition with improved selectivity, offering a favorable therapeutic profile for patients with specific B-cell malignancies. This medicine was US FDA-approved for MCL, WM, MZL, CLL/SLL, and FL.
Image from https://everyone.org/brukinsa-zanubrutinib.
Mechanism of Action
BTK is a critical component of the B-cell receptor (BCR) signaling and cytokine receptor pathways, essential for B-cell proliferation, trafficking, chemotaxis, and adhesion. Aberrant BTK activity is implicated in various B-cell malignancies. Zanubrutinib forms a covalent bond with the cysteine 481 residue in BTK's active site, leading to irreversible inhibition. This action disrupts downstream signaling pathways, including NF-κB and MAP kinase, thereby inhibiting malignant B-cell proliferation and survival, and reducing tumor growth.
Pharmacokinetics and Pharmacodynamics
Zanubrutinib exhibits high oral bioavailability and achieves sustained BTK occupancy in both blood and lymphoid tissues. Its pharmacokinetic profile supports twice-daily dosing, maintaining consistent BTK inhibition. The drug is metabolized primarily by cytochrome P450 3A (CYP3A), necessitating caution when co-administered with strong CYP3A inhibitors or inducers.
Usual Dosing
Adults: 160 mg twice daily or 320 mg once daily; continue until disease progression or unacceptable toxicity
Kidney Impairment: No dosage adjustments are provided on the manufacturer's labeling.
Hepatic Impairment:
Before treatment: For severe impairment (Child-Turcotte-Pugh class C), reduce dose to 80 mg twice daily and monitor for adverse reactions.
During treatment: For drug-induced liver injury, withhold if suspected and discontinue upon confirmation.
Administration: Administer with or without food. Swallow capsules whole with water; do not open, break, or chew capsules.
Dietary Considerations: Avoid grapefruit, grapefruit juice, and Seville oranges during therapy.
Clinical Efficacy
Zanubrutinib has demonstrated significant efficacy across multiple B-cell malignancies:
Mantle Cell Lymphoma (MCL): In a phase II trial involving 86 patients with relapsed/refractory MCL, zanubrutinib achieved an overall response rate (ORR) of 83.7%, with a complete response (CR) rate of 77.9%. The median progression-free survival (PFS) was 33.0 months.Blood
Waldenström's Macroglobulinemia (WM): The phase III ASPEN trial compared zanubrutinib to ibrutinib in patients with WM. Zanubrutinib demonstrated a higher very good partial response (VGPR) rate and a favorable safety profile, particularly regarding cardiac events. Blood
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Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL): In the phase III ALPINE trial, zanubrutinib showed superior PFS compared to ibrutinib in patients with relapsed/refractory CLL/SLL, especially among high-risk subgroups. NEJM
Image from https://www.nejm.org/doi/full/10.1056/NEJMoa2211582#ap0.
Follicular Lymphoma (FL): In the phase II ROSEWOOD trial, combining zanubrutinib with obinutuzumab had superior ORR compared to obinutuzumab alone, with a favorable benefit-risk profile. J Clin Oncol
Marginal Zone Lymphoma (MZL): In the phase II MAGNOLIA trial, zanubrutinib has higher ORR, with 73% of responders alive and progression-free, with a favorable safety/tolerability profile. Blood
Safety Profile
Zanubrutinib's safety profile is characterized by:
Hematologic Toxicities: Common adverse events include neutropenia, thrombocytopenia, and anemia. Leukocytosis and lymphocytosis can also occur. Regular monitoring of blood counts is recommended. Drugs.com
Infections: Patients may experience infections such as upper respiratory tract infections. Prompt evaluation and management of infectious symptoms are essential. Drugs.com
Bleeding Events: While less common, serious hemorrhagic events have been reported. Caution is advised when co-administering with anticoagulants or antiplatelet agents. Drugs.com
Cardiac Events: Incidences of atrial fibrillation and flutter are lower compared to first-generation BTK inhibitors, but vigilance remains necessary. Monitor for signs/symptoms of cardiac arrhythmias. Hypertension and peripheral edema can occur. Assess BP at baseline and each clinical visit (as well as weekly home monitoring for initial 3 months), obtain ECG at each clinical visit, and obtain a baseline echocardiography (transthoracic preferred) in high-risk patients. Blood
Hepatotoxicity: Severe, life-threatening, and potentially fatal drug-induced liver injury can occur. Monitor bilirubin and transaminases at baseline and periodically during treatment; monitor more frequently in patients with abnormal liver tests or signs/symptoms of toxicity.
Secondary Malignancies: Second primary malignancies, including non skin carcinoma can occur. The most common is nonmelanoma skin cancer. Advise patients to apply sunscreen.
Patient Selection and Clinical Considerations
Zanubrutinib is approved for:
MCL: For patients who have received at least one prior therapy.
WM: As a first-line treatment or for those with relapsed/refractory disease.
CLL/SLL: For treatment-naïve and relapsed/refractory patients.
FL: For relapsed/refractory patients, in combination with obinutuzumab, after ≥2 lines of systemic therapy who have received at least 1 anti–CD20–based regimen.
MZL: For relapsed/refractory patients.
When considering zanubrutinib, assess patient-specific factors such as comorbidities, concurrent medications, and prior treatment history. Its improved selectivity and safety profile make it a suitable option for patients at higher risk of adverse events with first-generation BTK inhibitors.
Zanubrutinib, a next-generation BTK inhibitor, is recommended by the NCCN guidelines as a treatment option for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). It is approved for both treatment-naive and relapsed/refractory CLL/SLL patients. Specifically, it is highlighted as an effective monotherapy, with evidence showing its ability to provide deep and durable responses, particularly for patients who may not tolerate other covalent BTK inhibitors like ibrutinib due to intolerance or resistance. This makes it a valuable choice in cases of del(17p)/TP53 mutation and other high-risk features.
Compared to other BTK inhibitors, zanubrutinib offers enhanced selectivity, which is associated with improved tolerability and fewer off-target side effects, such as atrial fibrillation. Additionally, the NCCN emphasizes that its use should align with patient-specific factors, such as comorbidities, prior treatment, and overall risk profile. As part of individualized care, clinicians are encouraged to consider zanubrutinib's favorable safety profile and efficacy when making treatment decisions for CLL/SLL patients.
According to the updated guidelines, zanubrutinib is now a preferred therapy for first-line treatment of patients with CLL/SLL who do not have the deletion(17p) / TP53 mutation; the recommendation is category 1. .
For patients with CLL/SLL without deletion(17p) / TP53 mutation who are receiving second-line or subsequent therapy, zanubrutinib was moved from “other recommended regimen” to “preferred regimen” (category 1). The statement that recommended zanubrutinib to patients with a contraindication to other BTK inhibitors was removed.
For those patients who have CLL/SLL with the deletion(17p) / TP53 mutation, zanubrutinib is now a preferred therapy in both first- and second-line treatment, according to the updated guidelines. Zanubrutinib is category 1 for second-line or subsequent therapy. Again, zanubrutinib was moved from “other recommended regimen” to “preferred regimen,” and the qualifying statement that the drug be given to patients with a contraindication to other BTK inhibitors was removed.
In addition, under special considerations for the use of small-molecule inhibitors, there is updated information on adverse events of special interest, based on evidence published in 2020 by Constantine Tam, MBBS, MD, a hematologist and CLL expert at the Peter MacCallum Cancer Centre in Victoria, Australia.
In December 2021, at the American Society of Hematology Meeting & Exposition in Atlanta, Tam presented results of the SEQUOIA trial, which found that zanubrutinib improved progression-free survival by 58% compared with bendamustine plus rituximab in patients with treatment-naïve CLL/SLL; Tam presented results from the cohorts of patients in SEQUOIA who did not have deletion(17p). The Lancet Oncology
For more information, please refer to the NCCN guidelines for CLL/SLL.
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Conclusion
Zanubrutinib represents a significant advancement in the management of B-cell malignancies, offering robust efficacy with a favorable safety profile. Its development reflects a commitment to optimizing targeted therapies, providing oncologists with an effective tool for treating complex hematologic cancers.
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