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Zanubrutinib shows sustained 6-year efficacy and safety in treatment-naive CLL/SLL, outperforming BR with durable PFS and high response rates.
Zanubrutinib (Brukinsa) continued to be efficacious and showcase sustained superiority over bendamustine plus rituximab (Rituxan; BR) in patients with treatment-naive chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), according to 6-year follow-up date from the phase 3 SEQUOIA study (NCT03336333) presented during the 2025 ASH Annual Meeting.1
At a median follow-up of 72.8 months, zanubrutinib led to a 72% reduction in the risk of disease progression or death vs BR in arms A and B (n = 241), which included patients without del(17p) (HR, 0.28; 95% CI, 0.20-0.38; P < .0001). The estimated 72-month progression-free survival (PFS) rate was higher with zanubrutinib vs BR, at 74% (95% CI, 67.2%-79.1%) vs 32% (95% CI, 25.2%-39.9%), respectively. When adjusted for COVID, the respective rates were 77% and 33%. In arm C (n = 111), which had a median follow-up of 76.7 months, the estimated 72-month PFS rate was 64% (95% CI, 53.6%-72.8%).
Moreover, the estimated 72-month PFS2 rate in arms A and B with zanubrutinib was 84% (95% CI, 78.2%-87.8%) vs 76% (95% CI, 69.9%-81.6%) with BR. In arm C, this rate was 82% (95% CI, 73.6%-88.3%). In terms of overall survival (OS), the estimated 72-month rates with zanubrutinib and BR were 84% and 80%, respectively, in arms A and B. After adjusting for COVID, these respective rates were 88% and 82%. In arm C, the 72-month OS rate was 83%, and 85% after adjusting for COVID.
In arms A and B, zanubrutinib elicited a higher overall response rate (ORR) than BR, at 98% vs 89%, respectively; the complete response (CR)/CR with incomplete hematopoietic recovery (CRi) rate was 24% in both arms. In arm C, zanubrutinib elicited an ORR of 97%, with a 21% CR/CRi rate. Lastly, the time to next treatment proved to be significantly longer in those who received zanubrutinib vs BR (HR, 0.22; 95% CI, 0.14-0.34; P < .0001). At 72 months, 89% (95% CI, 84.2%-92.6%) of patients who received zanubrutinib had not received subsequent treatment vs just 55% (95% CI, 47.7%-62.2%) of those given BR.
“At this long-term follow-up of 6 years, zanubrutinib continues to demonstrate robust efficacy and a favorable safety profile in treatment-naive CLL/SLL,” Constantine Tam, MBBS, MD, head of Lymphoma Service at Alfred Health and professor of Haematology at Monash University, in Melbourne, Australia, and coauthors wrote in a poster of the data. “In patients with del(17p), long-term outcomes [including PFS, PFS2, and OS] were robust and comparable to those in patients without del(17p), suggesting that zanubrutinib may ameliorate the historically poor prognosis associated with this high-risk feature…These long-term results continue to support zanubrutinib as an effective, tolerable frontline treatment option for treatment-naive CLL.”
The registrational phase 3 study enrolled patients with untreated CLL/SLL who met International Working Group on Chronic Lymphocytic Leukemia criteria for treatment and had measurable disease by CT/MRI and not suitable for fludarabine, cyclophosphamide, and rituximab.
Arms A and B underwent open-label randomization in a 1:1 fashion to receive zanubrutinib at 160 mg twice daily until disease progression, intolerable toxicity, or end of study, or BR for no more than 6 cycles. Arm C just received zanubrutinib at the same dose and schedule. Notably, those in arm B who experienced disease progression were permitted to cross over to arm A to receive next-line zanubrutinib before initiating any other therapy for CLL/SLL. Key end points in those arms were investigator-assessed PFS and ORR, as well as OS and safety. Investigators also evaluated PFS2.
In January 2023, the FDA approved zanubrutinib for the treatment of patients with CLL or SLL based on data from SEQUOIA.2 The median PFS was not reached (95% CI, not evaluable [NE]-NE) with zanubrutinib vs 33.7 months (95% CI, 28.1-NE) with BR (HR, 0.42; 95% CI, 0.28-0.63; P < .0001). Zanubrutinib elicited an ORR of 88% (95% CI, 81%-94%) with a median duration of response that was not reached by a median follow-up of 25.1 months.
Previous data from the trial showed that at a median follow-up of 26.2 months (IQR, 23.7-29.6), single-agent zanubrutinib led to superior PFS vs BR in those without del(17p) with a hazard ratio of 0.42 (95% CI, 0.28-0.63; P < .0001)3 sustained PFS benefit at a median follow-up of 61.2 months (HR, 0.29; 95% CI, 0.21-0.40; P = .0001.4 Moreover, in arm C, prior findings have indicated that with 5 years of follow-up, single-agent zanubrutinib led to an estimated 60-month PFS rate of 72.2% (95% CI, 62.4%-79.8%).5
Zanubrutinib was also found to have a consistent PFS benefit over BR irrespective of IGHV status. In those with IGHV-unmutated disease in arms A and B, the HR for PFS was 0.22 (P < .0001). In arm C, the PFS benefit derived with zanubrutinib was comparable between those with IGHV-mutated and -unmutated disease (HR, 1.21; P = .585). The estimated 72-month PFS rates in those with IGHV-mutated and -unmutated disease were 65% (95% CI, 47.1%-78.8%) and 64% (95% CI, 49.9%-75.4%), respectively.
The toxicity profile of zanubrutinib was comparable between arms A and C, and grade 3 or higher treatment-emergent toxicities occurred in 72% of those who received zanubrutinib in arm A, 74% of those given BR in arm B, and 74% of those who received zanubrutinib in arm C; they proved fatal for 10%, 3%, and 6% of patients, respectively. The most common toxicities that led to death were infections (arm A, 5%; arm C, 3%).
In arms A and B (n = 467), adverse effects of special interest (AESIs) of any grade were experienced by 93% of patients; they were grade 3 or higher for 59% of patients. The most common any-grade treatment-emergent and post-treatment AESIs reported in at least 15% of patients in arms A and B who received zanubrutinib vs BR were COVID (42% vs 14%), contusion (24% vs 4%), upper respiratory tract infection (21% vs 15%), hypertension (20% vs 13%), pneumonia (16% vs 12%), urinary tract infection (16% vs 10%), neutropenia (14% vs 46%), anemia (10% vs 21%), and basal cell carcinoma (10% vs 4%). The most common grade 3 or higher AESIs in these arms were hypertension (13% vs 7%), neutropenia (11% vs 41%), COVID (10% vs 2%), pneumonia (8% vs 5%), urinary tract infection (2% vs 3%), anemia (1% vs 3%), upper respiratory tract infection (1% vs 1%), and basal cell carcinoma (1% vs 0%).
In arm C (n = 11), AESIs of any grade occurred in 93% of patients, and they were grade 3 or higher for 59% of patients. The most common any grade or grade 3 or higher AESIs experienced with zanubrutinib were COVID (39%; 7%), upper respiratory tract infection (29%; 0%), contusion (22%; 0%), hypertension (19%; 10%), basal cell carcinoma (17%; 0%), pneumonia (16%; 6%), urinary tract infection (16%; 3%), neutropenia (12%; 11%), and anemia (10%; 0%).
With regard to exposure-adjusted incidence rates for select treatment-emergent toxicities, rates were low for atrial fibrillation and hypertension and comparable between arms A, B, and C. Moreover, neutropenia rates were lower with zanubrutinib vs BR, although rates of hemorrhage were higher.
“The safety profile of zanubrutinib remains consistent with prior reports,” the study authors concluded. “No new safety signals were observed.”
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