Dr. Shadman on the Efficacy and Safety of Zanubrutinib in CLL

Mazyar Shadman, MD, MPH, physician, associate professor, Division of Medical Oncology, University of Washington School of Medicine, associate professor, Clinical Research Division, Fred Hutchinson Cancer Center, discusses the efficacy and safety of zanubrutinib (Brukinsa) in chronic lymphocytic leukemia (CLL), as well as data derived from the agents use which supports the regulatory approval of zanubrutinib in this patient population.

In January 2023, the second-generation covalent BTK inhibitor was granted FDA approval for the treatment of patients with CLL or small lymphocytic lymphoma. The regulatory decision was supported by findings from both the phase 3 SEQUOIA (NCT03336333) and ALPINE (NCT03734016) trials.

Zanubrutinib's selectivity allows the agent to be well tolerated and reduces many of the off-target toxicities commonly associated with ibrutinib (Imbruvica), Shadman explains. It was hypothesized that zanubrutinib could produce beneficial efficacy in terms of exposure coverage and drug levels necessary to achieve responses, he notes.

The agent has shown promising efficacy the first-line setting, as evidenced by the SEQUOIA trial, Shadman continues. SEQUOIA is considered the largest prospective study conducted in patients with first-line CLL harboring 17p deletions, Shadman states. The trial enrolled patients who were deemed ineligible to receive fludarabine, cyclophosphamide, and rituximab (Rituxan) due to their age or comorbidities, he details. Patients without 17p deletions were randomly assigned to receive either single-agent zanubrutinib until disease progression or intolerance, or standard bendamustine plus rituximab (BR), he says. The study also included a cohort of patients with 17p deletions, all of whom received zanubrutinib monotherapy.

The primary analysis of SEQUOIA demonstrated that zanubrutinib improved median progression-free survival (PFS) vs BR in the randomized cohort of patients with treatment-naïve CLL/SLL, Shadman reports. At a median follow-up of 25.0 months, the median PFS was not reached in the experimental arm vs 33.7 months in the standard of care arm.

Extended follow-up data from SEQUOIA further demonstrated the survival benefit seen with zanubrutinib vs BR in patients with or without IGHVmutations, Shadman says. Historically, patients with 17p deletions/TP53mutations, followed by those with unmutated IGHV, experienced poor prognosis with chemotherapy-based regimens. Those with IGHV-mutated disease, however, typically experienced benefit with standard chemotherapy, he notes. Despite this, SEQUOIA confirmed the superiority of zanubrutinib over chemotherapy in that patient population, Shadman concludes.