Extended Follow-up of ALPINE Study Confirmed Superior PFS Benefit of Zanubrutinib Versus Ibrutinib in R/R CLL/SLL

In a head-to-head comparison of 2 Bruton tyrosine kinase (BTK) inhibitors zanubrutinib and ibrutinib in the randomized, phase 3 ALPINE study (NCT03734016), primary analysis demonstrated superiority of zanubrutinib over ibrutinib in terms of progression-free survival (PFS) and overall response rate (ORR), accompanied by favorable safety/tolerability profile, in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).¹ Results of an extended follow-up analysis (follow-up: 3 years) were reported at the 2023 American Society of Hematology annual meeting and summarized here.

The ALPINE study enrolled patients with R/R CLL/SLL, who received ≥1 prior therapy, and had measurable disease. Eligible patients were randomized 1:1 to receive zanubrutinib or ibrutinib.² Efficacy assessments included investigator-based PFS and ORR; sensitivity analyses were done to confirm PFS results. Data cut-off was 15 May 2023.²

A total of 652 evaluable patients were included in the study and were randomized to receive zanubrutinib (n=327) or ibrutinib (n=325). The median age was 67 in the zanubrutinib group and 68 in the ibrutinib group; a majority of patients had an Eastern Oncology Cooperative Group status of 1 in both cohorts.² At data cut-off (September 15, 2023), 59% of zanubrutinib-treated patients and 47% of ibrutinib-treated patients remained on therapy.²

At a median follow-up of 39 months, zanubrutinib continued to show superiority versus ibrutinib (hazard ratio [HR], 0.68; P=.0011), with PFS rates of 64.9% with zanubrutinib and 54.8% with ibrutinib.² The PFS benefits extended to other major subgroups, including in patients with del(17p)/TP53 mutations (HR, 0.52; P=.0047).² Sensitivity analysis (included only progression and death events that occurred on active treatment) confirmed the PFS benefit of zanubrutinib (HR, 0.69; P=.0206).² Zanubrutinib-treated patients achieved higher ORR compared to those treated with ibrutinib (90.2% vs 82.8%; P=.001).² With longer follow-up, deeper responses were achieved with zanubrutinib and ibrutinib treatments in terms of CR/CRi (10.4% vs. 7.1%).² The 36-month OS rates were similar in zanubrutinib and ibrutinib cohorts (82.5% vs 79.6%).²

In this extended follow-up, median treatment duration was 38.7 months in the zanubrutinib-treated cohort and 35 months in the ibrutinib-treated cohort.² The most common reasons for treatment discontinuation with zanubrutinib versus ibrutinib therapies were adverse events (AEs; 19.8% vs 26.2%).² In both zanubrutinib and ibrutinib cohorts, the most common AEs (any grade) were COVID-19, neutropenia, diarrhea, and upper respiratory tract infection.² Grade ≥3 AEs were similar with zanubrutinib versus ibrutinib; the most common grade ≥3 AEs were neutropenia (22.2% in both cohorts) and hypertension (16.4% vs 14.5%).² Rates of serious AEs were lower with zanubrutinib therapy (50.9% vs 59%) compared with ibrutinib.² Discontinuation rates due to cardiac disorders were lower with zanubrutinib (0.9% [n=3]) vs ibrutinib (4.6% [n=15]) and there were no fatal cardiac events with zanubrutinib (6 with ibrutinib).² Compared to the ibrutinib cohort, the incidence of cardiac events was lower with zanubrutinib in most categories, including atrial fibrillation/flutter (6.8% [n=22] vs 16.4% [n=53]; P<.0001).²

Based on this extended follow-up data, it was concluded that zanubrutinib continued to show PFS benefits and more favorable cardiac safety profile compared to ibrutinib therapy in patients with R/R CLL/SLL, with emergence of no new safety signals.

Source:

1. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388:319-332.
2. Brown J, Eichhorst B, Lamanna N, et al. Extended follow-up of ALPINE randomized phase 3 study confirms sustained superior progression-free survival of zanubrutinib versus ibrutinib for treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL). Presented at the 65th American Society of Hematology (ASH) Annual Meeting & Exposition, December 9-12, 2023; San Diego, CA: Abstract 2023.