SEQUOIA Long-Term Follow-Up and Zanubrutinib Monotherapy Data

Dr. Shadman reviews SEQUOIA 6-year follow-up data, highlighting that zanubrutinib monotherapy continues demonstrating high efficacy regardless of del(17p) status. Key outcomes include 74% PFS at 6 years for del(17p)-negative patients (Arm A) and 64% for del(17p)-positive patients (Arm C, 111 patients representing the largest prospective BTK inhibitor cohort in this high-risk population).

An important observation is the temporal separation between TP53 wild-type and del(17p) populations: through year 5, outcomes differ by only a few percentage points, with a 10% gap emerging at year 6. This delayed adverse predictive impact of del(17p) with continuous zanubrutinib contrasts with time-limited venetoclax-obinutuzumab data where outcomes diverge by year 4, informing treatment selection discussions.

PFS2 data (measuring time from study randomization through second-line treatment) demonstrates that starting with zanubrutinib produces superior combined outcomes compared to starting with bendamustine-rituximab then receiving novel agents. This addresses the historical argument of saving BTK inhibitors for second-line after initial chemotherapy.

Post-progression treatment documentation shows that over 75% of patients in the bendamustine-rituximab arm received BTK inhibitors at relapse, with approximately 6% receiving BCL-2 inhibitors and only 3% receiving chemotherapy, confirming excellent novel agent access and providing a plausible explanation for the absence of overall survival separation between arms. Dr. Lipsky notes that SEQUOIA's Arm C represents the largest prospective BTK inhibitor dataset for del(17p) patients with the longest follow-up, making it uniquely valuable despite inherent cross-arm comparison limitations.