Favourable outcomes with zanubrutinib versus ibrutinib in patients with r/r CLL

Interim results of the ALPINE study suggest that zanubrutinib exhibits superior efficacy and safety in patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) compared with ibrutinib.

Treatment of chronic CLL/SLL has been transformed with the advent of effective inhibitors of B-cell receptor signalling, such as Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib. Zanubrutinib is a potent, next-generation BTK inhibitor designed to maximise BTK occupancy and minimise off-target effects, which might minimise toxicities and improve efficacy compared with ibrutinib [1].

The phase 3, randomised ALPINE study (NCT03734016) compared zanubrutinib with ibrutinib in patients with relapsed or refractory (r/r) CLL or SLL with ≥1 prior lines of treatment and measurable lymphadenopathy. The participants (n=652) were randomised 1:1 to receive either 160 mg zanubrutinib twice daily or 420 mg ibrutinib once daily. The primary endpoint was overall response rate (ORR), non-inferiority, and superiority [2].

Prof. Peter Hillmen (University of Leeds, UK) presented the pre-planned interim analysis approximately 12 months after randomisation of the first 415 patients. Median follow-up with zanubrutinib (n=207) was 15.3 months and with ibrutinib (n=208) 15.4 months; 87.4% and 75.5%, respectively, remained on treatment. Discontinuation of treatment was mainly due to adverse events (AEs) in both arms.

ORR was 78.3% (95% CI 72.0–83.7) in the zanubrutinib arm and 62.5% (95% CI 55.5–69.1) in the ibrutinib arm, demonstrating superiority in the primary endpoint for zanubrutinib (P=0.0006). In a patient subset with 17p deletion, ORR was 83.3% in the zanubrutinib arm versus 53.8% in the ibrutinib arm. The event-free rate at 12-months was 94.9% versus 84.0% (HR 0.40; 95% CI 0.23–0.69; P=0.0007). Disease progression at 18 months was observed in 20 patients included in the zanubrutinib arm and in 42 patients included in the ibrutinib arm. There were no statistically significant differences in overall survival at this point (P=0.1081).

Safety analysis revealed that ≥95.6% of patients experienced any-grade AEs. Rates of serious AEs (27.5% in the zanubrutinib group vs 32.4% in the ibrutinib group), as well as fatal AEs (3.9% vs 5.8%, respectively) were similar in both groups. Treatment discontinuation due to AEs was less frequent in the zanubrutinib arm (7.8%) compared with the ibrutinib arm (13.0%), as was the occurrence of atrial fibrillation and flutter (2.5% vs 10.1%; P=0.0014).

Prof. Hillmen concluded, “In this interim analysis of the ALPINE study, zanubrutinib had a superior response rate, improved PFS, and a lower rate of atrial fibrillation and flutter. These data support that more selective BTK inhibition, with more complete and sustained BTK occupancy, results in improved efficacy and safety outcomes.”

1. 
   
   1. Tam CS, et al. Blood 2019;134(11):851–9.
   
   
   2. Hillmen P, et al. First interim analysis of ALPINE study: results of a phase 3 randomised study of zanubrutinib vs ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphcytic lymphoma. LB1900, EHA 2021 Virtual Congress, 9–17 June.

 

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Posted on 5 August, 2021