Zanubrutinib Shows Sustained PFS Benefit at 6 Years in SEQUOIA CLL Trial

Long-term follow-up from the randomized phase III SEQUOIA trial demonstrates that zanubrutinib provides a sustained improvement in progression-free survival (PFS) compared with bendamustine-rituximab in patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) without del(17p). At 6 years, the PFS rate for patients on zanubrutinib monotherapy (Arm A) was 74%, rising to approximately 77% with a COVID-19 adjusted analysis, versus 32% for those receiving bendamustine-rituximab.

In the non-randomized Arm C, which enrolled patients with del(17p), the 6-year PFS with zanubrutinib was 64%. While outcomes between TP53-wild-type and del(17p) patients appeared similar through year 5, a 10% difference emerged at year 6, indicating that the adverse predictive impact of del(17p) takes several years to manifest with continuous BTK inhibitor therapy.

The 78-month update added PFS2 data, which measured time from randomization through second-line therapy. Even when combining first- and second-line outcomes, patients who started with zanubrutinib fared better than those who began with chemoimmunotherapy. Post-progression treatment data showed that over 75% of patients in the bendamustine-rituximab arm received BTK inhibitors at relapse, approximately 6% received BCL-2 inhibitors, and only 3% received chemotherapy, which helps explain the absence of an overall survival difference between arms.

The SEQUOIA trial (NCT03336333) was an open-label study that randomized patients with treatment-naïve CLL/SLL without del(17p) to zanubrutinib or bendamustine-rituximab, while patients with del(17p) were enrolled in a separate zanubrutinib monotherapy cohort. These updated results were presented at the 2025 American Society of Hematology (ASH) Annual Meeting.