Five-Year SEQUOIA Data Show Zanubrutinib’s Durable Survival, Disease Control in High-Risk CLL/SLL

Zanubrutinib demonstrated strong, sustained efficacy in high-risk (17p deletion) treatment-naïve chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL), according to the results of a 5-year follow-up in arm C of the phase 3 SEQUOIA study. The progression-free survival (PFS) benefit in this arm was consistent with that observed in the randomized cohort of patients without del(17p) (arm A), with stable safety, validating the Bruton tyrosine kinase inhibitor’s value as a frontline choice for patients with CLL/SLL, regardless of del(17p) status. Constantine Tam, MD, of Alfred Hospital and Monash University, presented the updated findings from arm C, assessed as of April 30, 2024, at the 2025 ASCO Annual Meeting.

“For the first time, we’re showing that for patients with or without 17p deletion, they’re doing just as well with the same therapy,” Dr. Tam told Blood Cancers Today, in an interview.

Arm C is a nonrandomized cohort of 111 SEQUOIA participants with del(17p) CLL/SLL who enrolled between February 2018 and March 2019 and received zanubrutinib monotherapy until either unacceptable toxicity or disease progression. Per Tam, it represents the “largest cohort of uniformly treated patients with del(17p).”

The median age of participants in arm C was 71 years (range, 42-87 years). Most (67 patients, 60%) had unmutated immunoglobulin heavy-chain variable region gene (IGHV) disease, and 47 (42%) harbored both del(17p) and a TP53 mutation. Although unmutated IGHV, del(17p), and TP53 mutations are each independent poor prognostic markers in CLL/SLL associated with aggressive, difficult-to-treat disease, at a median follow-up of 65.8 months (range, 5-75 months), the median PFS was not reached. The estimated 60-month PFS rate was 72.2% (62.4%-79.8%), or 73.0% (63.3%-80.6%) when adjusted for COVID-19.

In arm A, five-year follow-up data demonstrated a similarly durable PFS benefit in patients with CLL/SLL without del(17p) who received single-agent zanubrutinib. The estimated 54- and 60-month PFS rates in arm A were 80% and 76%, respectively.

Median overall survival (OS) was also not reached in arm C, further solidifying the durability of zanubrutinib’s survival and disease control benefit. There, the estimated 60-month OS rate was 85.1% (76.9%-90.6%), or 87.0% (79.0%-92.1%) when adjusted for COVID-19.

Overall, nearly all participants responded positively to zanubrutinib (overall response rate, 97.3%), and 18.2% achieved deep remission, based on the study’s complete response/complete response with incomplete hematologic recovery rate of 18.2%. Zanubrutinib was ongoing in 62.2% of patients at the cutoff date.

No new safety signals emerged with longer-term follow-up. Adverse events (AEs; 17.1%) and disease progression (15.3%) were the most common causes of treatment discontinuation. The top three key AEs of interest (AEIs) included any-grade infection (82%), bleeding (60%), and neutropenia (19%). Infection (33%), neutropenia (16%), and hypertension (8%) were the three most frequently reported grade 3 and above AEIs.

“These are all real-world patients [who are] older and have comorbidities and who are not chemotherapy fit. Despite being older and unfit and having 17p deletion. They are having excellent survival and progression-free survival,” Tam said in the interview.