Zanubrutinib Demonstrates Long-Term Efficacy, Safety in Relapsed/Refractory CLL/SLL

Zanubrutinib (Brukinsa) displayed durable efficacy with a sustained progression-free survival (PFS) benefit in patients with relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), according to findings from the BGB-3111-LTE1 study (NCT04170283), which was a long-term extension of the phase 3 ALPINE study (NCT03734016) presented during the 2025 ASH Annual Meeting & Exposition.¹

At the April 1, 2025, data cutoff, with a median follow-up of 54.2 months (range, 0.1-73.5), findings from LTE1 showed that patients who received zanubrutinib (n = 327) experienced a median PFS of 52.5 moths (95% CI, 49.7-65.8). The median PFS after adjusting for COVID-19 was 60.3 months (95% CI, 49.9-not reached [NR]). The 60-month PFS rate was 47.3% (95% CI, 41.5%-52.9%); this rate was 50.4% (95% CI, 44.4%-56.1%) when adjusted for deaths due to COVID-19.

“With up to 6 years of follow-up, zanubrutinib continued to demonstrate durable efficacy and a sustained PFS of approximately 5 years in patients with relapsed/refractory CLL,” Constantine Tam, MD, MBBS, the head of the Lymphoma Service at Alfred Health, and a professor of hematology at Monash University in Melbourne, Australia, said during a poster presentation of the data. “Most patients who crossed over from the zanubrutinib arm of ALPINE remained on zanubrutinib in the long-term extension study.”

What were the design characteristics of ALPINE and LTE1?

ALPINE was an open-label, randomized trial that enrolled patients with relapsed/refractory CLL/SLL at 113 sites globally.² Patients needed to be at least 18 years old, have a confirmed diagnosis per International Workshop on CLL criteria, be refractory to at least 1 prior line of therapy, and have measurable disease on imaging. LTE1 include 189 patients; 176 patients continued receiving zanubrutinib at their last ALPINE dose and 13 entered survival follow-up.¹

Patients received zanubrutinib at 160 mg twice daily. The primary end point was safety.³ Secondary end points included investigator-assessed PFS, investigator-assessed duration of response, and overall survival (OS).

At baseline, patients who received zanubrutinib in ALPINE had a median age of 67 years (range, 35-90).¹ Most patients were male (65.1%), White (79.8%), had an ECOG performance status of 1 (58.4%), had Binet stage A or B or Ann Arbor stage I or II disease (55.7%), and had normal or not deleted 17p mutation status (86.2%). The median number of prior lines of therapy was 1 (range, 1-6).

What were the long-term safety data and additional efficacy findings?

Additional findings from LTE1 demonstrated that the complete response (CR)/CR with incomplete bone marrow recovery (CRi) rate was 12.8% (95% CI, 9.4%-17.0%), an increase from 11.6% with approximately 12 months of extended follow-up. Four patients who had a partial response since the closure of ALPINE achieved a CR/CRi. The median PFS among 45 patients with del(17p) was 49.9 months (95% CI, 33.3-NR). The median PFS in these patients following adjustment for COVID-19 was 50.2 months (95% CI, 33.3-NR). The 60-month PFS rates overall and following adjustment for COVID-19 were 38.2% (95% CI, 23.4%-52.9%) and 40.5% (95% CI, 25.0%-55.5%), respectively.

The median treatment exposure among all patients treated with zanubrutinib in ALPINE and LTE1 was 52.5 months (range, 0.39-73.4) and 79.9% of patients received the agent for at least 24 months.

The safety profile of zanubrutinib in the del(17p) population was comparable with that of the overall safety analysis set. The most common any-grade treatment-emergent adverse effects (TEAEs) included COVID-19 (42.3%), upper respiratory tract infection (32.7%), hypertension (27.5%), and neutropenia (25.6%). Any-grade TEAEs occurred in 99.7% of patients; grade 3 or higher TEAEs occurred in 79.0% of patients. Grade 3 or greater treatment-related TEAEs (42.3%), serious TEAEs (60.2%), fatal TEAEs (14.5%), and TEAEs leading to treatment discontinuation (20.4%) were reported.

Adverse effects (AEs) of special interest during years 0 to 1 included infections (50.0%), hemorrhage (37.3%), and neutropenia (25.0%). Patients who received treatment up to 5 to 6 years (n = 98) experienced infections (41.8%), serious infections (6.1%), and hemorrhage (6.1%).

“Most AEs of key interest are either stable or declined over time,” Tam said. “With the longest reported follow-up to date, patients with del(17p) had an efficacy and safety profile similar to the overall population. In aggregate, these data support zanubrutinib as an effective treatment in patients with relapsed/refractory CLL.”

Disclosures: Tam noted that the study was sponsored by BeOne Medicines Ltd.

References

1. Tam C, Mital A, Weinkove R, et al. 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). Blood. 2025;146(suppl 1):2123. doi:10.1182/blood-2025-2123
2. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388(4):319-332. doi:10.1056/NEJMoa2211582
3. Long-term extension study of zanubrutinib (BGB-3111) regimens in participants with B-cell malignancies. ClinicalTrials.gov. Updated October 21, 2025. Accessed December 7, 2025. https://clinicaltrials.gov/study/NCT04170283