Zanubrutinib plus venetoclax produces high response rate in treatment-naive CLL/SLL patients

Based onSEQUOIA submitted in 2025 Zanubrutinib plus venetoclax showed strong response rates in patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), results from a phase 3 trial (NCT03336333).

At a median follow-up of 31.2 months (range, 0.4-58.0), the objective response rate (ORR) of patients in Group D (n=114) was 97.4%. Furthermore, the ORR in patients with 17p deletion and/or TP53 wild-type disease (n=66) was 98.5%, whereas in patients without 17p deletion or TP53 mutant disease (n=47), the ORR was 95.7%. The complete response (CR)/CR of the overall population was 48.3%, of which the complete response rates in the 17p deletion and/or TP53 wild-type disease group and the disease group without 17p deletion or TP53 mutant disease were 47.0% and 48.9%, respectively. Other data showed that the rate of undetectable minimal residual disease (MRD) in the peripheral blood of patients was 59%, of which 60% did not have TP53 wild-type disease and/or 17p deletion, and 59% had 17p deletion and/or TP53 mutation disease. The 24-month progression-free survival (PFS) rates of each group were 92% (95% CI, 85%-96%), 89% (95% CI, 76%-95%), and 94% (95% CI-85%-98%), respectively.

Cohort D of the [Phase 3] SEQUIOA study demonstrated that zanubrutinib plus venetoclax had robust efficacy and produced deep and durable responses in naive CLL regardless of the presence of [17p deletion] or TP53 mutations. The rate of [undetected] MRD in peripheral blood was up to 59%...[and] the safety profile was favorable, with no new safety signals [identified].

Patients in Arm D of the SEQUOIA trial received zanubrutinib plus venetoclax 160 mg twice daily, increasing from cycles 4 to 28 to 400 mg once daily. After cycle 28, zanubrutinib monotherapy was administered until disease progression, unacceptable toxicity, or both drugs reaching an undetectable MRD in peripheral blood and bone marrow in two consecutive tests at least 12 weeks apart.

Total58% of the patient population had 17p deletions and/or TP53 mutations, and 41% expressed neither. The median age was 67 years (range: 26-87 years), 56% of patients were male, and 75% had unmutated immunoglobulin heavy chain variable status. A total of 98% of patients had an ECOG performance status of 0 or 1, a median creatinine clearance of 76 mL/min (range, 25-355), and 37% of patients had 17p deletions and TP53 mutations.

TrialEnd points for Arm D include investigator-assessed progression-free survival, investigator-assessed ORR, overall survival, undetected MRD rate, and safety.

The most common treatment-associated adverse events (TEAEs) of any particle size included COVID-19 infection (54%), diarrhea (41%), bruising (32%), and nausea (30%). Additionally, the most common grade 3 or higher TEAEs included neutropenia (17%), hypertension (10%), and diarrhea (6%). A total of five patients died from adverse events.

The study was designed to better determineB-cell lymphoma and the efficacy of Bruton's tyrosine kinase inhibitors (TKIs) in patients with CLL or SLL who have 17p deletions or TP53 mutations. Previous studies found that zanubrutinib monotherapy showed enhanced PFS results in CLL/SLL and was the only Bruton TKI shown to be superior to ibrutinib (Imbruvica) in a phase 3 trial, including those with high-risk 17p deletions.

References:https://www.onclive.com/view/zanubrutinib-plus-venetoclax-yields-high-response-rates-in-treatment-naive-cll-sll