SEQUOIA : Results of a Phase 3 Randomised Study of Zanubrutinib versus Bendamustine + Rituximab in Patients with Treatment-Naive Chronic Lymphocytic Leukaemia/Small Lymphocytic Lymphoma.

Abstract

Zanubrutinib (zanu) is a selective nextgeneration Bruton tyrosine kinase (BTK) inhibitor designed to have high specificity for BTK and minimal off-target effects. SEQUOIA (NCT03336333) is an open-label, global phase 3 study that randomised treatment naive (TN) patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) without del(17p) to receive zanu 160 mg twice daily until progressive disease or unacceptable toxicity, or bendamustine 90 mg/m2 on day 1 and 2 and rituximab 375 mg/m2 in cycle 1, 500 mg/m2 in cycles 2-6 for 6 x 28-day cycles (BR). Adult patients who met International Workshop on CLL (iwCLL) criteria for treatment were eligible if they were >= 65 years or unsuitable for treatment with fludarabine, cyclophosphamide and rituximab. Central verification of del(17p) status by fluorescence in situ hybridisation was required. Patients were stratified by age (<65 years vs. >=65 years), Binet Stage (C vs. A/B), immunoglobulin heavy chain gene (IGHV) mutational status and geographical region. The primary end-point was independent review committee (IRC)-assessed progression-free survival (PFS). Secondary end-points included PFS by investigator assessment (INV), overall response rate (ORR; by IRC and INV), overall survival (OS) and safety. Responses for CLL and SLL were assessed per modified iwCLL criteria and Lugano criteria respectively. Adverse events (AEs) were recorded until disease progression. From 31 Oct 2017-22 Jul 2019, 479 patients without del(17p) were randomised to zanu ( n = 241) and BR ( n = 238). Treatment groups were well balanced for demographical and disease characteristics (zanu vs. BR): median age, 70.0 years vs. 70.0 years; unmutated IGHV, 53.4% (125/234) vs. 52.4% (121/231); and del(11q), 17.8% vs. 19.3%. At median followup (26.2 months), PFS was significantly prolonged with zanu versus BR as assessed by IRC (hazard ratio [HR] 0.42, 95% CI 0.28-0.63, 2-sided p < 0.0001), and INV (HR 0.42, 95% CI 0.27-0.66, 2-sided p = 0.0001). Treatment benefit for zanu was observed across subgroups for age, Binet stage, bulky disease and del(11q) status and for patients with unmutated IGHV (HR 0.24, 2-sided p < 0.0001), but not for mutated IGHV (HR 0.67, 2-sided p = 0.1858). Estimated 24-mo PFS (IRC) (zanu vs. BR) was 85.5% (95% CI 80.1%-89.6%) vs. 69.5% (95% CI 62.4%-75.5%); ORR by IRC was 94.6% (95% CI 91.0%-97.1%) vs. 85.3% (95% CI 80.1%-89.5%); complete response rate was 6.6% vs. 15.1%; ORR by INV was 97.5% (95% CI 94.7%-99.1%) vs. 88.7% (95% CI 83.9%-92.4%); estimated 24-mo OS was 94.3% (95% CI 90.4%-96.7%) vs. 94.6% (95% CI 90.6%-96.9%). AEs of interest occurring during the full reporting period (pooled terms, zanu vs. BR) included atrial fibrillation (any grade [gr]: 3.3% vs. 2.6%), bleeding (any gr/gr>=3: 45.0%/3.8% vs. 11.0%/1.8%), hypertension (any gr: 14.2% vs. 10.6%), infection (any gr/gr>=3: 62.1%/16.3% vs. 55.9%/18.9%) and neutropenia (any gr/gr>=3: 15.8%/11.7% vs. 56.8%/51.1%). Treatment discontinuation due to AEs occurred in 20 patients (8.3%) vs. 31 patients (13.7%) (zanu vs. BR) and AEs leading to death occurred in 11 patients (4.6%) vs. 12 patients (5.3%). No sudden deaths were reported. In this global registrational trial, zanu demonstrated statistically significant improvement in PFS compared with BR as assessed by IRC. Superiority was also observed in PFS by INV and ORR by IRC and INV. Zanu was well tolerated, with low rates of atrial fibrillation. These data support the potential utility of zanu in the frontline management of patients with TN CLL/SLL.