Abstract
Introduction: The SEQUOIA study (NCT03336333) evaluated zanu, a next-generation Bruton tyrosine kinase (BTK) inhibitor, in TN CLL/SLL. The study included 4 tx arms; this report focuses on: arm A (zanu monotherapy [mono]) vs arm B (BR) and the non-randomized arm C [zanu mono in pts with del(17p)]. Previous analyses at 60 months (mo) follow-up (FU) showed that zanu provided sustained progression-free survival (PFS) superiority over BR and robust, durable efficacy in pts with del(17p). Here, the updated efficacy and safety results for arms A vs B and arm C with a median FU of ~6yrs (>12mo of additional FU) are presented.
Methods: Pts without del(17p) were randomized to receive continuous zanu (arm A) or 6 cycles of BR (arm B). Pts in the BR arm could cross over to zanu after disease progression. Pts with del(17p) received continuous zanu in arm C. Adverse events (AEs) were reported until disease progression or start of next-line tx. This analysis evaluated efficacy and safety, including investigator-assessed PFS, time to next tx (TTNT), time to second PFS event or death (PFS2), and overall survival (OS). PFS and OS analyses were also adjusted for COVID-19 impact.
Results: In arms A and B, 479 pts received zanu (n=241) or BR (n=238). As previously reported, arms A and B were well balanced for demographic and disease characteristics. As of April 30, 2025, median FU was 72.8mo (range, 0.0-90.0). Zanu demonstrated sustained PFS superiority vs BR (HR, 0.28; 95% CI, 0.20-0.38; P<.0001). Estimated 72mo PFS rates were 74% (95% CI, 67.2-79.1) for zanu and 32% (95% CI, 25.2-39.9) for BR; after COVID-19 adjustment, rates were 77% (95% CI, 70.1-81.8) and 33% (95% CI, 25.5-40.4), respectively. Fewer zanu-treated pts required subsequent tx (n=27) vs BR-treated patients (n=84, including 67 who crossed-over). TTNT was significantly longer with zanu vs BR (HR, 0.22; 95% CI, 0.14-0.34; P<.0001); at 72mo, 89% (95% CI, 84.2-92.6) and 55% (95% CI, 47.7-62.2) of pts that received zanu and BR, respectively, had not initiated subsequent tx. Estimated 72mo PFS2 rates were 84% (95% CI, 78.2-87.8) for zanu and 76% (95% CI, 69.9-81.6) for BR. OS at 72mo was 84% (95% CI, 78.7-88.2) for zanu and 80% (95% CI, 74.4-85.2) for BR; after adjusting for COVID-19, OS was 88% (95% CI, 82.5-91.2) and 82% (95% CI, 76.1-86.7), respectively. Median tx exposure for zanu was 71.8mo (range, 0.5-89.9) and 6.0mo (range, 0.9-7.4) for BR. Grade ≥3 tx-emergent AEs (TEAEs) occurred in 72% of zanu pts and 74% of BR pts, and serious AEs occurred in 61% and 41%, respectively. The exposure-adjusted incidence rates (EAIR) for AEs of interest (per 100 person-mo) were atrial fibrillation/flutter (zanu vs BR: 0.16 vs 0.10), hypertension (0.46 vs 0.36) and infections (3.40 vs 3.37), which were comparable between zanu and BR, while neutropenia (2.95 vs 0.34) was higher for BR and both hemorrhage (1.57 vs 0.32) and major hemorrhage (0.18 vs 0.05) were higher with zanu.
Arm C included 111 pts [110 with confirmed del(17p)] who received zanu and had a median FU of 76.7mo (range, 5.0-86.9). Estimated PFS rate at 72mo was 64% (95% CI, 53.6-72.8) and after COVID-19 adjustment was 65% (95% CI, 54.3-73.5). In arm C, 22 pts started new tx. At 72mo, 83% of pts (95% CI, 73.6-88.6) had not yet initiated subsequent tx. Estimated 72mo PFS2, OS and OS with COVID-19 adjusted rates were 82% (95% CI, 73.6-88.3), 83.2% (95% CI, 74.7-89.1) and 85.0% (95% CI, 76.7-90.5), respectively. Median tx exposure in arm C was 74.8mo (range, 1.6-86.8). The observed safety profile in arm C was similar to arm A. In arm C, 74% and 62% of pts experienced grade ≥3 and serious TEAEs, respectively. The EAIR for select AEs of interest (per 100 person-mo) were atrial fibrillation/flutter 0.15, hypertension 0.38, infections 4.16, neutropenia 0.35, hemorrhage 2.03 and major hemorrhage 0.17.
Conclusion: With 6 years of FU, zanu continues to demonstrate robust efficacy and a favorable safety profile in TN CLL/SLL. Zanu demonstrated sustained superiority vs BR with a 72% reduction in risk of progression or death and 78% reduction in risk of needing subsequent tx. Among pts with del(17p), long-term outcomes (including PFS, PFS2, and OS) were robust and comparable to those without del(17p), suggesting that zanu may ameliorate the historically poor prognosis associated with this high-risk feature. This supports zanu as an effective, tolerable frontline tx option for TN CLL/SLL, including those with high-risk features.
