A Bruton’s tyrosine kinase inhibitor.
Brukinsa tradename.
Zanubrutinib approved for chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
It inhibits BTK irreversibly at the cysteine residue 481.
Has a more specific target binding profile than Ibrutinib.
Considered a second generation irreversible BTK inhibitor.
Has fewer off target effects on related enzymes, with fewer side effects than ibrutinib..
It may be combined with monoclonal antibodies better than with ibrutinib.
Well absorbed, with clinical dose 160 mg b.i.d. achieving drug exposures 6-10 times higher than ibrutinib.
Early studies suggest effectiveness in CLL, Waldenstrom’s Macroglobulinemia, and lymphomas.
Approved for the treatment of CLL/small lymphocytic lymphoma, Waldenström’s macroglobulinemia, mantle cell lymphoma and marginal zone lymphoma.
Side effects include bruising and bleeding.
Atroal fibrillation rate lower than with Ibrutinib.
In refractory CLL response rate 94% with progression free survial 100% at 12 months and 95% at 24 months.
74.2% overall response rate (ORR), 24.2% having a complete response and 33 experiencing a partial response, 50.0%.
Patients maintaining their response at 6 months comprised 79.0% of responders.
The progression-free survival rates at 6 and 9 months were 80.0% and 67.0%, respectively.
Most patients were still alive at 1 year, for a 12-month overall survival rate of 94.0%.
Adverse effects: diarrhea (20.6%), contusion (19.1%), constipation (13.2%), neutropenia (13.2%), pyrexia (11.8%), upper respiratory tract infection (11.8%), thrombocytopenia (10.3%), and nausea (10.3%).
Grade 3 or greater adverse effects occurred in 38.2% of patients, with events of neutropenia (10.3%), diarrhea (2.9%), pyrexia (2.9%), thrombocytopenia (2.9%), anemia (2.9%), and pneumonia (2.9%).
Patients were treated with zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity.
Associated with high overall response rate and durable responses in patients with CLL or small lymphocytic lymphoma.
Trade name Brukinsa.
The SEQUOIA study and AU-013 study response rates for zanubrutinib ranged from 92.7% in patients with treatment-naïve CLL or SLL and deletion 17p (del 17p) in the SEQUOIA study to 100% in treatment-naïve patients and 95% in the relapsed or refractory setting in the AU-013 study.
The efficacy of zanubrutinib in patients with treatment-naïve CLL/SLL was evaluated in SEQUOIA.
In the randomized cohort, a total of 479 patients without 17p deletion were randomized 1:1 to receive either zanubrutinib until disease progression or unacceptable toxicity, or bendamustine plus rituximab for 6 cycles.
The main efficacy outcome measure was progression-free survival (PFS).
The median PFS was not reached in the zanubrutinib arm and was 33.7 months in the bendamustine plus rituximab arm.
In a separate non-randomized cohort of SEQUOIA, zanubrutinib was evaluated in 110 patients with previously untreated CLL/SLL with 17p deletion.
Overall response rate (ORR) per IRC was 88%.
The median duration of response (DOR) was not reached after a median follow-up of 25.1 months.
Well-tolerated and active in patients with CLL or SLL, irrespective of del 17p status, with very high response rates.
The efficacy of zanubrutinib in patients with relapsed or refractory (R/R) CLL/SLL was evaluated in the ALPINE trial.
A total of 652 patients were randomized 1:1 to receive either zanubrutinib or ibrutinib.
The median number of prior lines of therapy was 1.
The main efficacy outcome measures at the time of response analysis were ORR and DOR.
The ORR was 80% in the zanubrutinib arm and 73% in the ibrutinib arm.
The median DOR was not reached in either arm, after a median follow-up of 14.1 months.
The most common adverse reactions (≥30%) were decreased neutrophil count (42%), upper respiratory tract infection (39%), decreased platelet count (34%), hemorrhage (30%), and musculoskeletal pain (30%).
Second primary malignancies, including non-skin carcinomas, developed in 13% of patients.
Atrial fibrillation or flutter were reported in 3.7% of patients, and grade ≥3 arrhythmias in 0.2% of patients.
Ibrutinib (Imbruvica) was the first BTK inhibitor approved by the FDA for CLL or SLL, followed by the approval of the second-generation BTK inhibitor, acalabrutinib (Calquence).
It is a next-generation BTK inhibitor, with pharmacodynamic and pharmacokinetic advantages over ibrutinib.
The most common adverse events were confusion and upper respiratory tract infection.
The ORR was 100% among 11 patients who received front-line treatment with zanubrutinib, including 5 (22.7%) complete responses and 17 (77.3%) partial responses.
The ORR was 95% in the relapsed or refractory setting, including 13.9% complete responses, 72.3% partial responses, and 8 partial responses with lymphocytosis.
All patients continue to respond.
The 12- and 24-month progression-free survival rates were 95% and 97%, respectively, in treatment-naïve patients, and 97% and 91%, respectively, in those with relapsed or refractory disease.
At a median follow-up of 2.5 years, 100% of patients had an adverse event.
Discontinuation rates and rates of atrial fibrillation are less with this agent than with ibrutinib.
The most common adverse events were contusion (47.2%), upper respiratory tract infection (42.3%), Its use is supported for first loin option in most CLL settings with ineficacy comparable to debt of other drugs of the family and potentially lower risk of some adverse events.diarrhea (31.7%), cough (29.3%), headache (23.6%), and fatigue (20.3%). Grade ≥3 atrial fibrillation occurred in 1.6% of patients.
Its use is supported for first line option in most CLL settings with ineficacy comparable to debt of other drugs of the family and potentially lower risk of some adverse events.
It has demonstrated improvement in progression free survival compared with Bendamustine-rituximab in older patients with those with comorbidities with treatment naïve CLL.
In patients with relapsed or refractory CLL or small lymphocytic lymphoma, progression,free, survival is significantly longer among patients who received zanubrutinib than among those who received Ibrutinib and zanubrutinib was associated with fewer cardiac adverse events (Brown JR).