ASH 2022: Next-Generation BTKi Zanubrutinib Demonstrates Improved Efficacy and Tolerability Compared with Ibrutinib

The Bruton tyrosine kinase inhibitor (BTKi) ibrutinib (Imbruvica) has become the standard treatment for relapsed/refractory chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL) but can cause unwanted off-target effects. Investigators therefore sought to compare the efficacy and safety of ibrutinib with the next-generation BTKi zanubrutinib (Brukinsa), which has greater specificity for cancer cell types.

Final results from the phase III ALPINE study, presented by Jennifer Brown, MD, PhD, an LRF Scientific
Advisory Board (SAB) member, included 652 patients with relapsed or refractory CLL or SLL. Patients received either zanubrutinib or ibrutinib until disease progression or unacceptable toxicity. Approximately 23% of patients who received ibrutinib discontinued treatment due to adverse events compared with 16% in the zanubrutinib group.

Over 29.6 months of follow-up, zanubrutinib use lowered the likelihood of disease progression by 35% compared with ibrutinib. Progression events occurred in 26.9% of zanubrutinib-treated patients compared with 36.9% in the ibrutinib group. Overall response rates in the zanubrutinib group were also higher – 86.2% vs 75.5% in the ibrutinib group. Results were similar in patients with high-risk disease features.

Severe or serious adverse events were more frequent among ibrutinib-treated patients than those who received zanubrutinib, leading to fewer dose interruptions and reductions. Discontinuation due to cardiac toxicity was lower in the zanubrutinib group (0.3%) than the ibrutinib group (4.3%), and no fatal cardiac events were observed among zanubrutinib-treated patients (six occurred in the ibrutinib group).

The investigators concluded that these results suggest zanubrutinib is both more effective and better tolerated than ibrutinib in patients with relapsed/refractory CLL or SLL, leading to lower rates of discontinuation and fewer cardiac complications.

This study also included contributions from past SAB member Susan O’Brien, MD of the University of California, Irvine.