Zanubrutinib Shows Superior Progression-Free Survival vs Ibrutinib in Chronic Lymphocytic Leukemia

Zanubrutinib (Brukinsa) is a small molecule Bruton’s tyrosine kinase inhibitor under evaluation as a monotherapy and in combination with other treatments for various B-cell malignancies.

Zanubrutinib (Brukinsa) was found to produce superior progression-free survival (PFS) compared with ibrutinib (Imbruvica) in patients with chronic lymphocytic leukemia (CLL), according to findings from the final analysis of the phase 3 ALPINE trial as assessed by an independent review committee (IRC). The trial showed that zanubrutinib was generally well tolerated with safety findings at the final PFS analysis consistent with what was previously reported in clinical trials.1

“This positive result adds to the growing body of evidence underpinning our belief in the potential for Brukinsa to provide new hope for CLL patients facing this intractable disease. With this final PFS analysis, Brukinsa has achieved superior [PFS], as well as superiority in overall response rate versus ibrutinib,” said Mehrdad Mobasher, MD, MPH, chief medical officer, Hematology at BeiGene, said in a press release. “We look forward to sharing the full results with the medical and patient communities and will submit for presentation at a medical congress and for publication.”1

Zanubrutinib is a small molecule Bruton’s tyrosine kinase (BTK) inhibitor under evaluation as a monotherapy and in combination with other treatments for various B-cell malignancies. After oral administration, the median time to maximum concentration is 2 hours, and the elimination half-life is approximately 2 to 4 hours. Zanubrutinib is metabolized primarily by cytochrome P450 (CYP) 3A.2

In the randomized, global ALPINE trial (NCT03734016), zanubrutinib was compared with ibrutinib in previously treated patients with relapsed or refractory CLL or small lymphocytic leumkemia (SLL).

Investigators randomized 652 patients from Europe (60%), the United States (17%), China (14%), New Zealand and Australia (9%) across 2 cohorts. One cohort was administered zanubrutinib 160 mg orally twice daily while the other was administered ibrutinib 420 mg orally once daily until disease progression or unacceptable toxicity.

The trial’s primary endpoint was overall response rate (ORR) as defined by pre-specified non-inferiority of zanubrutinib compared with ibrutinib assessed by investigator and IRC using modified 2008 iwCLL guidelines, with modification for treatment-related lymphocytosis for patients with CLL, and per Lugano Classification for non-Hodgkin lymphoma for patients with SLL.

Key secondary endpoints were PFS and event rate of atrial fibrillation or flutter. Additional secondary endpoints included duration of response, overall survival, and incidence of adverse events (AEs).

In the analysis, zanubrutinib demonstrated a statistically significant decreased risk of atrial fibrillation or flutter, which is characterized by an irregular heartbeat that can cause blood clots, stroke, heart failure, and other heart-related conditions.3

By investigator assessment, the data demonstrated superior ORR due to the statistically significant improvement in ORR for zanubrutinib compared with ibrutinib (p = 0.0006). Additionally, by IRC, there was a numerically higher ORR but not statistically significant improvement (p = 0.0121 compared to the 2-sided stringent statistical boundary of p < 0.0099 set for the interim analysis).3

Overall, the investigators found that zanubrutinib had a safety profile that was consistent with what was observed in the previously conducted clinical development program. The most common AEs are decreased lymphocyte count, decreased neutrophil count, decreased platelet count, hemorrhage, musculoskeletal pain, rash, and upper-respiratory tract infection.2

BeiGene’s supplemental New Drug Application for zanubrutinib for adult patients with CLL or SLL has a target action date of January 20, 2023.


1. BeiGene Announces Positive Topline Results from Final Progression-Free Survival Analysis of BRUKINSA® (zanubrutinib) Compared to IMBRUVICA® (ibrutinib) in Phase 3 Chronic Lymphocytic Leukemia (CLL) Trial. BeiGene. News release. October 12, 2022.

2. U.S. FDA grants Brukinsa (zanubrutinib) accelerated approval in relapsed or refractory marginal zone lymphoma. News release. BeiGene, Ltd; September 15, 2021.

3. BRUKINSA® (Zanubrutinib) Demonstrates Superior Objective Response Rate by Investigator Assessment and Reduced Rates of Atrial Fibrillation or Flutter at Interim Analysis in Head-to-Head Trial Against Ibrutinib in Chronic Lymphocytic Leukemia. Cambridge, MA: BeiGene; April 28, 2021.