The primary analysis of the SEQUOIA trial demonstrated favourable safety and efficacy outcomes for the Bruton’s tyrosine kinase (BTK) inhibitor zanubrutinib compared to bendamustine-rituximab (BR) in treatment-naïve patients with chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL)1. However, long-term exposure data of BTK inhibitors in this setting is still limited. The median 5-year follow-up data from SEQUOIA were recently published in JCO2.
Study Design
The phase III SEQUOIA trial investigated zanubrutinib versus BR in treatment-naïve patients with CLL/SLL without del(17p). Patients were ≥65 years or ≥18 years with comorbidities, and had ≥1 International Workshop on CLL indication for treatment. Patients were randomly assigned (1:1) to receive oral zanubrutinib 160 mg twice daily in 28-day cycles until disease progression or unacceptable toxicity or BR intravenously for six cycles. BR-treated patients with disease progression were allowed to cross over to zanubrutinib. The primary endpoint was progression-free survival (PFS).
Results
Baseline demographics and disease characteristics were similar across patients treated with zanubrutinib (N= 241) and BR (N= 238). At a median follow-up of 61.2 months, 32% of zanubrutinib-treated patients had discontinued treatment and 79% had completed six cycles of BR.
Median PFS was significantly longer in zanubrutinib-treated patients compared to those treated with BR (not reached versus 44.1 months, HR[95%CI]: 0.29[0.21-0.40], p< 0.0001). Prolonged PFS with zanubrutinib was observed in both patient with mutated immunoglobulin heavy-chain variable region (IGHV) genes (HR, 0.40; one-sided p= 0.0003) and those with unmutated IGHV genes (HR, 0.21; one-sided p< 0.0001). Estimated 60-month overall survival (OS) rates were 85.8% and 85.0% in zanubrutinib- and BR-treated patients. Median OS was not reached in either treatment arm (HR[95%CI]: 0.89[0.55-1.43], p= 0.3090).
The safety profile of zanubrutinib was consistent with the primary analysis; rates of atrial fibrillation/flutter with zanubrutinib remained low (7.1%). Grade ≥3 treatment-emergent AEs of interest (AEIs) with zanubrutinib and BR included infection (30.0% versus 22.5%), neutropenia (12.5% versus 51.1%), bleeding (7.5% versus 1.8%), thrombocytopenia (2.5% versus 8.4%), and anaemia (0.8% versus 2.6%).
Conclusion
The extended follow-up confirmed the PFS benefit of zanubrutinib as previously reported in the primary analysis. In addition, no new safety findings were detected. These findings continue to support zanubrutinib as a treatment option for treatment-naïve patients with CLL/SLL.
References
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