Long-Term Efficacy Data on Zanubrutinib from SEQUOIA

Dr. Lipsky reviews the ELEVATE-TN trial supporting acalabrutinib approval in frontline CLL, 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.

Dr. Shadman 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% 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 versus 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 combining first and second-line outcomes, patients starting with zanubrutinib did better than those starting with chemoimmunotherapy. Post-progression treatment data showed that the majority of chemotherapy arm patients (over 75%) received BTKis at relapse, with approximately 6% receiving BCL-2 inhibitors and only 3% receiving chemotherapy, demonstrating excellent access to novel agents and explaining the lack of overall survival difference between arms.