Safety Analysis Finds Zanubrutinib’s Toxicity Profile Is Consistent With Other BTK Inhibitors

Zanubrutinib monotherapy in B-cell malignancies has a toxicity profile consistent with other Bruton tyrosine kinase (BTK) inhibitors, although it has a lower incidence of atrial fibrillation and hypertension than previously reported with ibrutinib, according to a pooled safety analysis.

The findings were published in Blood Advances and included data pooled from 6 studies with a total of 779 participants.

Ibrutinib was the first BTK inhibitor and has resulted in treatment limiting toxicities potentially due to off-target inhibition, the authors explained. Zanubrutinib, a second-generation BTK inhibitor, “exhibits less inhibition of off-target kinases than ibrutinib,” they wrote.

The median patient age across all trials was 65 years and 70% were male. One-third of patients (33%) had Waldenström macroglobulinemia (WM), 29% had chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and 19% had mantle cell lymphoma (MCL).

Most of the patients (85%) across the trials received zanubrutinib 160 mg twice daily and 13% received 320 mg once daily. More than half (55%) were treated for 2 or more years. Among patients who discontinued zanubrutinib, 27% did so because of progressive disease.

Nearly all (98%) of patients across all trials had reported 1 or more treatment-emergent adverse events (TEAEs). The most common non-hematologic toxicities were upper respiratory tract infection (39%), rash (27%), bruising (25%), musculoskeletal pain (24%), diarrhea (23%), cough (21%), and pneumonia (21%).

Two-thirds (66%) of patients experienced at least 1 grade ≥ 3 TEAE. Pneumonia (11%) and hypertension (5%) were the most commonly reported grade ≥ 3 non-hematologic TEAEs. Patients ≥ 75 years old were more likely to experience both grade ≥ 3 TEAEs and serious AEs than patients between the age of 65 and 75.

Only 10% of patients discontinued zanubrutinib as a result of TEAEs, most commonly for pneumonia and hemorrhage. Only 8% of patients had at least 1 dose reduction with the most common TEAEs leading to dose reduction being neutropenia, diarrhea, and pneumonia.

For the 38% of patients who had at least 1 treatment interruption due to TEAEs, 45% lasted ≤ 7 days, 23% lasted 8 to 14 days, and 32% lasted ≥ 15 days. Interruptions that lasted ≥ 15 days were most commonly associated with pneumonia, hepatitis B virus infection/reactivation, and neutropenia.

Nearly all (92%) patients had at least 1 adverse event of interest (AEI). AEIs were based on the known toxicity profile for BTK inhibitors. Patients with CLL/SLL and WM were more likely to have infections than patients with MCL. More than half (55%) of patients reported bruising or bleeding events. Patients ≥ 75 years old and who had CLL/SLL were more likely to experience bleeding events than patients with MCL and WM.

“One important observation supported by our analysis is confirmation of a lower risk of atrial fibrillation among zanubrutinib versus ibrutinib-treated patients,” the authors wrote.

Twelve percent of patients experienced all grade hypertension and 3% of patients experienced atrial fibrillation or flutter. Atrial fibrillation was more common in older patients (9% of patients ≥ 75 years, 3% of patients ≥ 65-75 years, and 0.3% of patients < 65 years).

The researchers noted that the small number of Black patients in the studies (1%) was one limitation, as well as the small number of patients with severe renal and hepatic impairment. They also explained that the frequencies of toxicities reported in the clinical trials may underestimate those in a real-world setting.

The authors concluded that “zanubrutinib may offer the potential for improved safety and tolerability in patients with B-cell malignancies relative to existing treatment options.”

Reference

Tam CS, Dimopoulos MA, Garcia-Sanz R, et al. Pooled safety analysis of zanubrutinib monotherapy in patients with B-cell malignancies. Blood Adv. Published online November 1, 2021. doi:10.1182/bloodadvances.2021005621