Zanubrutinib Represents Viable Treatment Option for Acalabrutinib-Intolerant B-cell Malignancies

Mazyar Shadman, MD MPH

Treatment with zanubrutinib (Brukinsa) maintained or improved response without an increase in acalabrutinib (Calquence) intolerance events in patients with previously treated B-cell malignancies, according to findings from a phase 2 study (NCT04116437) presented at the 2022 Pan Pacific Lymphoma Meeting.

In the analysis, patients who were intolerant to the Bruton tyrosine kinase (BTK) inhibitor acalabrutinib (n = 13) were assigned to receive either 160 mg of zanubrutinib twice daily or 320 mg once daily. Among the treated patients, 73% did not experience recurrence of acalabrutinib intolerance events. Of the patients who did experience a recurrence, 23% of events were at the same level as with acalabrutinib and 4% were at a lower grade.

“Of the acalabrutinib intolerance events that recurred, most (83%) recurred at the same severity; no events recurred at a higher severity,” the study authors wrote in a poster of the findings.

The most common acalabrutinib intolerances were arthralgia (n = 4), myalgia (n = 3), headache (n = 2), and hemorrhage (n = 2). Regarding arthralgia, 3 of the 4 patients did not experience a recurrence with zanubrutinib and 1 patient experienced a recurrence at the same grade. For myalgia, 1 patient experienced the event at a lower grade, 1 at the same grade, and 1 did not experience recurrence. For both headache and hemorrhage, 1 patient each did not experience recurrence and 1 patient each experienced the event at the same grade.

At a median follow-up of 12.9 months (range, 0.8-16.0), 10 patients remained on treatment. Among the 3 patients who discontinued treatment, 1 patient withdrew, 1 patient experienced progressive disease and died more than 30 days after the last dose, and the final patient discontinued because of myalgia at the same grade with acalabrutinib.

The median duration of treatment with zanubrutinib was 9.2 months (range, 0.5-16.0).

Investigators also reported efficacy outcomes for 10 treated patients. The overall response rate was 70% with a disease control rate of 80%. In terms of response, 60% of patients had a partial response or a very good partial response, 1 patient had a partial response with lymphocytosis and 1 patient had stable disease. One patient had progressive disease and 1 patient was not assessed.

The median time to best overall response was 5.9 months (range, 2.8-11.1) with a median time to first overall response of 3.0 months (range, 2.7-11.1).

“Zanubrutinib effectively maintained response in 80% and improved response from baseline in 70% of patients. These data suggest that zanubrutinib may provide a therapeutic option in patients intolerant to acalabrutinib across B-cell malignancies,” the authors wrote.

The single‑arm, open‑label, multicenter study in the United States evaluated the safety and efficacy of zanubrutinib in patients with previously treated B‑cell malignancies who are intolerant to ibrutinib and/or acalabrutinib.

The eligibility criteria for acalabrutinib intolerance was defined as nonhematologic toxicity grade 1 or higher for longer than 7 days; nonhematologic toxicity of at least grade 1 for any duration with at least 3 recurrent episodes; grade 3 or higher nonhematologic toxicity for any duration; grade 3 neutropenia with infection or fever; grade 4 hematologic toxicity that persists until BTK inhibitor therapy is discontinued due to toxicity; patients’ inability to use acid‑reducing agents or anticoagulants due to current BTK inhibitor use; resolution of grade 2 or higher BTK inhibitor toxicities to at least grade 1 or baseline and resolution of grade 1 BTK inhibitor toxicities to grade 0 or baseline before initiating zanubrutinib treatment.

Patients who experienced disease progression on prior BTK inhibitor were excluded from the trial.

At baseline, more than half of patients had chronic lymphocytic leukemia (54%). Other disease indications included small lymphocytic lymphoma (15%), Waldenström macroglobulinemia (15%), mantle cell lymphoma (8%), and marginal zone lymphoma (8%). The median age was 73 years (range, 51-83).

The median number of prior therapies was 2 (range, 1-6). All patients received prior acalabrutinib and 62% had prior ibrutinib (Imbruvica). The median cumulative exposure to acalabrutinib was 4.6 months (range, 0.5‑26.9).

All-grade adverse events (AEs) that occurred with zanubrutinib included fatigue (31%), myalgia (31%), arthralgia (25%), contusion (25%), back pain (15%), cough (15%), decreased appetite (15%), dyspnea (15%) decreased neutrophil count (15%) oropharyngeal pain (15%), pain in extremities (15%), palpitations (15%), pyrexia (15%), and rash (15%). Grade 3 AEs included both incidences of decreased neutrophil count and 1 incident each of COVID‑19, febrile neutropenia, gastroenteritis salmonella, and hypertension.

Investigators noted that bleeding events occurred in 4 patients and included contusion, epistaxis, and hematoma. Infections occurred in 6 (46%) patients and included cellulitis, COVID‑19, COVID‑19 pneumonia, diverticulitis, fungal-skin infection, gastroenteritis salmonella, and urinary tract infection.

Of note, investigators reported that no atrial fibrillation, anemia, or thrombocytopenia/platelet count decrease occurred in any patient.

Dose reductions because of AEs were reported among 15% of patients and 54% of patients experienced dose interruptions.

An exploratory biomarker analysis showed that relapse on zanubrutinib was associated

with BTK inhibitor–resistant mutations—3 of 5 patients who progressed had BTK/PLCG2 mutations at/after progression.

Reference

Shadman M, Flinn IW, Kingsley EC, et al. Zanubrutinib in 13 acalabrutinib‑intolerant patients with B‑cell malignancies. Presented at: 2022 Pan Pacific Lymphoma Conference. July 18-22, 2022; Koloa, Hawaii.