Zanubrutinib (BGB-3111) is an investigational, next-generation irreversible Bruton’s tyrosine kinase inhibitor that was shown to be highly potent and selective in nonclinical studies. Early studies have shown that zanubrutinib yields durable clinical responses in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Based on these promising results, an ongoing global, open-label, multicenter phase 3 study (SEQUOIA, BGB-3111-304; NCT03336333) that included a nonrandomized cohort (Arm C) is evaluating zanubrutinib monotherapy in treatment-naïve (TN) patients with del(17p) CLL/SLL; the initial results of this study were presented at the 2019 ASH annual meeting and are summarized here.
In the SEQUOIA trial, eligible patients were adults with CLL/SLL who met International Workshop on Chronic Lymphocytic Leukemia criteria for treatment and were either aged ≥65 years or were unsuitable for treatment with fludarabine, cyclophosphamide, and rituximab. Entry into Arm C required central verification of del(17p) by fluorescence in situ hybridization, with a minimum of 7% aberrant nuclei present. Enrolled patients were administered zanubrutinib 160 mg twice daily.
A total of 109 patients with centrally confirmed del(17p) were enrolled into Arm C; 106 patients remained on study treatment at data cutoff (April 19, 2019). Median age was 70.0 years (range, 42-86); 66% had del(13q), 34% had del(11q), and 61.5% had unmutated IGHV disease.
All patients had received ≥1 doses of zanubrutinib and were included in the safety analysis. The most common any-grade adverse events (AEs), regardless of causality, occurring in ≥7.5% included contusion, rash, upper respiratory tract infection, and nausea. Grade ≥3 AEs occurred in 40 patients (36.7%), and included neutropenia/decreased neutrophil count (n = 11), pneumonia (n = 4), and hypertension (n = 3). One fatality was reported due to grade 5 pneumonia that occurred 8 days after the last dose of zanubrutinib; serious AEs were reported in 24% of patients (n = 26). AEs of interest included infections, bruising, minor bleeding, neutropenia, arthralgia/myalgia , diarrhea, anemia, hypertension, thrombocytopenia, fatigue, headache, petechiae, second primary malignancy, and major bleeding. Atrial fibrillation (grade 3) was reported in 1 patient.
Overall, 109 patients were evaluable for efficacy with median follow-up of 10.0 months; 104 of these patients continued on the study treatment. The overall response rate was 92.7% (n = 101), including a complete response rate of 2% (n = 2), partial response (PR) rate of 78.9% (n = 86), and PR with lymphocytosis rate of 11.9% (n = 13); disease stabilization was noted in 5.6% (n = 6) of patients. Disease progression due to Richter transformation was reported in 2 patients.
Preliminary results of the prospective SEQUOIA trial suggested that zanubrutinib was active and generally well tolerated in TN patients with del(17p) CLL/SLL.
Tam CS, et al. ASH Abstract 499. Session 642.