Monica D. Mead, MD, discusses the efficacy and safety differences between the second-generation BTK inhibitor zanubrutinib and the first-generation BTK inhibitor ibrutinib in patients with mantle cell lymphoma.
Monica D. Mead, MD, assistant clinical professor, medicine, Hematologic Malignancy, the University of California, Los Angeles (UCLA), UCLA Health, UCLA Jonsson Comprehensive Cancer Center, discusses the efficacy and safety differences between the second-generation BTK inhibitor zanubrutinib (Brukinsa) and the first-generation BTK inhibitor ibrutinib (Imbruvica) in patients with mantle cell lymphoma (MCL).
As a second-generation BTK inhibitor, zanubrutinib binds to BTK proteins with greater precision than ibrutinib, Mead says. Since zanubrutinib does not bind to some of the off-target receptors that ibrutinib binds to, it has a more favorable toxicity profile, Mead explains. The binding precision of zanubrutinib also allows for a more favorable pharmacokinetic profile. Accordingly, treatment with zanubrutinib induces earlier, deeper responses than treatment with ibrutinib, according to Mead.
Clinical trials investigating zanubrutinib currently have shorter follow-up intervals compared with trials evaluating ibrutinib, Mead notes. However, in ibrutinib trials, longer follow-up correlated with deeper responses. Similar response patterns have emerged in the zanubrutinib trials as well, Mead says.
The phase 1/2 BGB-3111-AU-003 trial (NCT02343120) investigated zanubrutinib in patients with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. Extended follow-up data from this trial provide evidence that complete response rates in patients with hematologic malignancies treated with zanubrutinib increase over time, Mead explains. Moreover, long-term findings from the single-arm, phase 2 BGB-3111-206 trial (NCT03206970), which supported the 2019 FDA approval of zanubrutinib in patients with relapsed/refractory MCL, showed that 83.7% of patients responded with the agent at a median follow-up of 35.3 months. The median duration of response was not reached.
Overall, zanubrutinib has produced early responses with a tolerable safety profile in patients with MCL, Mead emphasizes. Zanubrutinib is also associated with fewer adverse effects (AEs) of interest than ibrutinib, Mead notes. In BGB-3111-206, the most common AEs of grade 3 or higher were decreased neutrophil counts (18.6%) and pneumonia (12.8%). Conversely, the toxicity profile of ibrutinib in the confirmatory phase 3 SHINE trial (NCT01776840) informed AbbVie’s voluntary withdrawal of the FDA indication for the agent in patients with relapsed/refractory MCL.