Long-Term Efficacy Data on Zanubrutinib From SEQUOIA

Andrew Lipsky, MD, reviews the ELEVATE-TN trial supporting acalabrutinib approval in frontline chronic lymphocytic leukemia, demonstrating superiority over chlorambucil-obinutuzumab. He notes a potential but underpowered efficacy advantage for acalabrutinib plus obinutuzumab over acalabrutinib monotherapy while acknowledging that both approaches demonstrate excellent tolerability and efficacy.

Mazyar Shadman, MD, MPH, details the SEQUOIA study for zanubrutinib, which compared against bendamustine-rituximab as the chemoimmunotherapy control arm. The study design excluded patients with del(17p) from randomization (arm C, 111 patients), given the known inefficacy of chemoimmunotherapy in that population. With 6 years of follow-up, arm A (zanubrutinib monotherapy in patients without del[17p]) shows 74% progression-free survival (PFS), rising to approximately 77% with COVID-19 adjustment analysis.

For arm C (del[17p] patients), the 6-year data shows 64% PFS. Importantly, through year 5, TP53 wild-type and del(17p) patients had similar outcomes, but at year 6, a 10% difference emerges, illustrating that the adverse predictive impact of del(17p) requires years to manifest, appearing at year 6 with zanubrutinib monotherapy vs year 4 with time-limited options.

The 78-month SEQUOIA update at ASCO 2026 added PFS2 data, measuring time from randomization through second-line therapy, and showed that even when combining first- and second-line outcomes, patients starting with zanubrutinib did better than those starting with chemoimmunotherapy. Postprogression treatment data showed that the majority of patients in the chemotherapy arm (over 75%) received Bruton tyrosine kinase inhibitors at relapse, with approximately 6% receiving BCL2 inhibitors and only 3% receiving chemotherapy, demonstrating excellent access to novel agents and explaining the lack of overall survival difference between arms.