Zanubrutinib Shows Sustained Efficacy in Chronic Lymphocytic Leukemia

“The key takeaway is that this is the largest cohort of patients with CLL [harboring] 17p deletions treated with single therapy on a prospective study, and at the median follow-up of 5 years, the PFS [rate] was 72.2%, which is not different from patients [with CLL/SLL] without 17p deletions treated with the same therapy,” according to lead study author Constantine S. Tam, MBBS, MD.

After 5 years of follow-up, sustained efficacy was observed in patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) who received treatment with zanubrutinib (Brukinsa), according to a presentation on findings from arm C of the phase 3 SEQUOIA trial (NCT03336333) presented during the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.1

Findings showed that patients with CLL/SLL harboring 17p deletions (n = 110) achieved a 5-year progression-free survival (PFS) rate of 72.2% (95% CI, 62.4%-79.8%); this rate was 73.0% (95% CI, 63.3%-80.6%) when adjusting for COVID-19. Of note, the median PFS was not reached with zanubrutinib at the data cutoff of April 30, 2024. Per IGHV mutation status, the 5-year PFS rate for patients with mutated IGHV (n = 36) and unmutated IGHV (n = 67) was 74.6% (95% CI, 56.9%-85.9%) and 70.7% (95% CI, 57.4%-80.6%), respectively.

“The key takeaway is that this is the largest cohort of patients with CLL [harboring] 17p deletions treated with single therapy on a prospective study, and at the median follow-up of 5 years, the PFS [rate] was 72.2%, which is not different from patients [with CLL/SLL] without 17p deletions treated with the same therapy,” lead study author Constantine S. Tam, MBBS, MD, said during a presentation at the meeting.

Tam is the head of the Lymphoma Service at Alfred Health and a professor of hematology at Monash University in Melbourne, Australia.

SEQUOIA Background and Design

The open-label, multicenter study included 4 arms: A and B, which randomly assigned patients without 17p deletions to receive zanubrutinib or bendamustine plus rituximab (Rituxan); arm C included patients with 17p deletions who were all treated with zanubrutinib; and arm D, which included patients with 17p deletions and/or TP53 mutations, who received zanubrutinib plus venetoclax (Venclexta).

At a median follow-up of 26.2 months (interquartile range, 23.7-29.6), the median PFS per independent review committee was not reached in arm A (95% CI, not estimable [NE]-NE) or arm B (95% CI, 28.1-NE).2 However, PFS was significantly improved in arm A compared with arm B (HR, 0.42; 95% CI, 0.28-0.63; 2-sided P < .0001). Data from arms A and B helped support the January 2023 FDA approval of zanubrutinib for the treatment of patients with CLL or SLL.3

All arms of the study included patients with CLL/SLL who were naive to treatment, met International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria for treatment, had measurable disease per CT and MRI, and were not candidates for fludarabine, cyclophosphamide, and rituximab.1

In arm C, patients were treated with zanubrutinib at 160 mg twice daily until disease progression, unacceptable toxicity, or the end of the study. Specifically for arm C, sensitivity analyses were performed for PFS and overall survival (OS) to account for deaths due to COVID-19, which were censored at the time of death if no prior disease progression was reported. Furthermore, response assessments were performed every 12 weeks following the first dose of the study drug for 96 weeks, then every 24 weeks until disease progression.

Of note, patients in arm C were enrolled between February 2018 and March 2019 and had a median study follow-up of 65.8 months (range, 50.0-75.0); during this time, 111 patients initiated zanubrutinib. Treatment was discontinued in 42 patients due to adverse effects (AEs; n = 19), disease progression (n = 3), investigator’s discretion (n = 3), and withdrawal by patient (n = 3); 69 patients remained on therapy.

The primary end points for arm C were investigator-assessed PFS, investigator-assessed objective response rate (ORR), OS, and safety.

Baseline Patient Characteristics

In arm C, the median age was 71 years (range, 42-87), and 85.6% were 65 years of age or older. The majority were male (71.2%) and had an ECOG performance status of 0 or 1 (87.3%). Most patients had CLL (90.1%), and 9.9% had SLL. Moreover, bulky disease included a longest diameter (LDi) of 5 cm or greater (39.6%) and a LDi of 10 cm or greater (10.8%). The median time from initial diagnosis was 21.39 months. Additionally, the majority of patients had 17p deletions (99.1%); 42.3% had both 17p deletions and TP53 mutations; most patients had unmutated IGHV (60.4%). Notably, complex karyotypes included those with 3 or more abnormalities (27.9%) and 5 or more abnormalities (18.9%).

Additional Efficacy and Safety Data

The 5-year OS rate was 85.1% (95% CI, 76.9%-90.6%) and 87.0% (95% CI, 79.0%-92.1%) with the COVID-19 adjustment. However, the median OS was not reached with zanubrutinib; 18 deaths occurred during the study. Furthermore, the ORR was 97.3%, with the best overall responses including complete remission (CR) and complete remission with incomplete count recovery (CRi; 18.2%), partial response (76.4%), stable disease (1.8%), and progressive disease (0.9%).

Of note, there were no new safety signals identified with longer-term follow-up. Treatment-emergent AEs (TEAEs) reported in at least 15% of patients included COVID-19 (grade 1/2, 26%; grade ≥3, 7%), upper respiratory tract infection (28%; 0%), arthralgia (25%; 1%), diarrhea (21%; 1%), contusion (22%; 0%), back pain (18%; 1%), constipation (19%; 0%), nausea (17%; 1%), cough (18%; 0%), basal cell carcinoma (17%; 0%), rash (17%; 0%), fall (12%; 5%), hypertension (9%; 7%), UTI (13%; 3%), and pneumonia (9%; 6%). TEAEs of special interest included infections (49%; 33%), hemorrhage (54%; 6%), second primary malignancies (23%; 7%), skin cancers (22%; 2%), neutropenia (3%; 16%), hypertension (10%; 8%), major hemorrhage (3%; 6%), anemia (9%), thrombocytopenia (6%; 2%), atrial fibrillation (3%; 5%), tumor lysis syndrome (1%; 0%), opportunistic infections (0%; 1%).

References

1. Tam CSL, Ghia P, Shadman M, et al. SEQUOIA 5-year follow-up in arm C: frontline zanubrutinib monotherapy in patients with del(17p) and treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). J Clin Oncol. 2025;43(suppl 16):7011. doi:10.1200/JCO.2025.43.16_suppl.7011
2. Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23(8):1031-1043. doi:10.1016/S1470-2045(22)00293-5
3. FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. FDA. January 19, 2023. Accessed May 31, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanubrutinib-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma