Long-term results of patients receiving zanubrutinib in the phase 3 ALPINE study confirm sustained benefit of zanubrutinib in patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (R/R CLL/SLL): Up to 6 years of follow-up with the long-term extension (LTE1)

Abstract

Abstract Background: Bruton tyrosine kinase (BTK) inhibitors are a standard of care in CLL. Zanubrutinib, a next-generation BTK inhibitor, was designed for greater BTK specificity and potency than ibrutinib to reduce off-target toxicities and improve efficacy. In the phase 3 ALPINE study (BGB-3111-305; NCT03734016), zanubrutinib demonstrated statistically and clinically significant superiority over ibrutinib in progression-free survival (PFS) and overall response rate, with a favorable safety profile in patients with R/R CLL/SLL. Upon completion of the ALPINE study, eligible patients from both treatment arms who chose to continue participation were enrolled in the long-term extension study LTE1 (BGB-3111-LTE1; NCT04170283) for ongoing zanubrutinib treatment or survival follow-up. Here, we report an update of patients initially enrolled in the zanubrutinib arm of ALPINE who continued to LTE1, which includes a total of 6 years of follow-up. Methods: This ad hoc analysis included all 327 patients in the zanubrutinib arm of ALPINE, incorporating long-term follow-up data for patients who enrolled in LTE1. In LTE1, patients continued zanubrutinib at their last ALPINE dose. Safety was assessed every 3 months (treatment-emergent adverse events [TEAEs] graded per Common Terminology Criteria for Adverse Events v5.0) and efficacy was assessed at least every 6 months per standard of care with regular restaging scans occurring at investigators' discretion; however, disease progression was confirmed. Results: Of the 327 patients enrolled in the zanubrutinib arm of ALPINE (324 treated), 189 enrolled in LTE1 (176 continued zanubrutinib, 13 entered survival follow-up only) between November 9, 2023, and February 28, 2024. The baseline characteristics of the 327 patients were previously reported (Brown N Engl J Med. 2023); the median age was 67.0 years (range, 35-90), with one median prior therapy line (mean, 1.7; range, 1-6). Del17p was present in 13.8% of patients. As of April 1, 2025, the median follow-up time (ALPINE + LTE1) was 54.2 months (range, 0.1-73.5). With up to 73.5 months of follow-up post-randomization from ALPINE, the median PFS for all patients was 52.5 months; the 60-month PFS rate was 47.3% (50.4% adjusted for COVID-19). Among patients with del17p, the median PFS was 49.9 months; the 60-month PFS rate was 38.2% (40.5% adjusted for COVID-19). With approximately 12 months of extended follow-up, the complete response (CR) with incomplete bone marrow recovery (CRi) rate continued to increase to 12.8% (95% confidence interval 9.4-17.0) from 11.6% in the last report, with four patients previously assessed with partial response having achieved CR/CRi (three with CR and one with CRi) since the study closure of ALPINE. Among the 324 patients in ALPINE+LTE1, the median treatment exposure was 52.5 months (range, 0.39-73.4) with 259 patients (79.9%) treated with zanubrutinib for ≥24 months. The median exposure among the 45 patients with del17p was 40.7 months (range, 0.39-73.4). Serious adverse events (AEs) occurred in 60.2% of patients (n=195), Grade ≥3 AEs occurred in 79% (n=259), with treatment-related Grade ≥3 AEs in 42.3% (n=137), and 20.4% discontinued due to AEs. Fatal TEAEs occurred in 14.5% of patients with the most frequent causes of death being infections (9%). The safety profile in the del17p population was comparable to the overall safety analysis set. With longer follow-up, the prevalence of most AEs of special interest remained stable year-over-year. Conclusion: With up to 6 years of follow-up in patients with R/R CLL/SLL, zanubrutinib continued to demonstrate durable efficacy with sustained PFS benefit and a consistent safety profile. Most patients from the zanubrutinib arm in ALPINE remain on zanubrutinib in LTE1. With the longest reported follow-up to date, patients with del17p demonstrated sustained efficacy similar to the overall population.