Phase III ALPINE Data Suggest Zanubrutinib Is Superior to Ibrutinib in CLL/SLL

By Cecilia Brown - Last Updated: December 20, 2022

Zanubrutinib may be “more efficacious and better tolerated” than ibrutinib as a treatment for patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to a final analysis of the phase III ALPINE study.1

Jennifer Brown, MD, PhD, of the Dana-Farber Cancer Institute, and colleagues conducted the study.

The study included 652 patients with relapsed/refractory CLL or SLL who received at least one prior line of therapy and had measurable disease. The researchers randomized patients 1:1 to receive zanubrutinib (n=327) or ibrutinib (n=325) until disease progression or unacceptable toxicity occurred. Both treatment arms included similar proportions of patients aged 65 years and older, male patients, patients with unmutated IGHV, patients with del(17p), and patients who had a TP53 mutation without del(17p). Patients in both treatment arms had a median of one prior line of therapy.

Patients who received zanubrutinib had superior progression-free survival (PFS) compared with those who received ibrutinib in the intention to treat population at a median follow-up of 29.6 months (hazard ratio [HR], 0.65; 95% CI, 0.49-0.86; two-sided P=.0024), when assessed by an independent review committee. The median PFS was 35 months in patients who received ibrutinib, while it was not reached in patients who received zanubrutinib.

Patients treated with zanubrutinib had a higher overall response rate (ORR) as assessed by an independent review committee, with an ORR of 86.2% compared with an ORR of 75.7% in the group that received ibrutinib (nominal two-sided P=.0007).

In patients with del(17p)/TP53 mutation, those who received zanubrutinib had a longer PFS than those who received ibrutinib, per assessment by an independent review committee.

“PFS, regardless of [independent review committee] or [investigator] assessment, consistently favored zanubrutinib across other major predefined subgroups, including IGHV status,” Dr. Brown and colleagues wrote.1

More patients who received ibrutinib (41.2%) discontinued treatment than those who received zanubrutinib (26.3%). Adverse events led to treatment discontinuation in 16.2% of patients receiving zanubrutinib and in 22.8% of patients receiving ibrutinib, while progressive disease led to treatment discontinuation in 7.3% and 12.9%, respectively.

Cardiac disorders led to treatment discontinuation in 4.3% of patients receiving ibrutinib and in 0.3% of those receiving zanubrutinib. Patients who received ibrutinib had a higher rate of atrial fibrillation/flutter (13.3%) than those receiving ibrutinib (5.2%). None of the patients who received zanubrutinib had grade five adverse events due to cardiac disorders, while 1.9% of those who received ibrutinib did.

Patients treated with ibrutinib had higher rates of grade three or higher adverse events, serious adverse events, dose interruption, and dose reduction than patients who received zanubrutinib.

Deaths occurred in 14.7% of patients who received zanubrutinib and in 18.5% who received ibrutinib (overall survival HR, 0.76; 95% CI, 0.51-1.11).

“As ALPINE is the first study to demonstrate PFS superiority in a head-to-head comparison of [Bruton tyrosine kinase] inhibitors, zanubrutinib has now proven superiority to ibrutinib in both ORR and PFS in [patients] with [relapsed/refractory] CLL/SLL. Efficacy benefits with zanubrutinib were observed across all major subgroups, including high-risk [patients],” Dr. Brown and colleagues concluded.1 “Zanubrutinib had a favorable safety profile compared with ibrutinib, with a lower rate of treatment discontinuation and fewer cardiac disorder events, including fewer cardiac events leading to death.”


  1. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib demonstrates superior progression-free survival (PFS) compared with ibrutinib for treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL): results from final analysis of ALPINE randomized phase 3 study. Abstract # LBA-6. Presented at the 64th ASH Annual Meeting and Exposition; December 10-13, 2022; New Orleans, Louisiana.
  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
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