BeiGene announced that the U.S. Food and Drug Administration (FDA) has approved its Bruton's tyrosine kinase inhibitor (BTKi)BRUKINSA (zanubrutinib) for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The U.S. approval is based on two global Phase 3 clinical trials demonstrating superior efficacy and a favorable safety profile for BRUKINSA in CLL: With a median follow-up of 26.2 months in the SEQUOIA trial, BRUKINSA demonstrated a significant PFS benefit versus bendamustine plus rituximab, (HR 0.42, [95% CI: 0.28, 0.63], P<0.0001), as assessed by an Independent Review Committee (IRC) in the first-line treatment setting. BRUKINSA achieved a superior overall response rate versus ibrutinib in the relapsed/refractory (R/R) treatment setting (ORR 80.4% vs 72.9%, P=0.0264), as assessed by an IRC in the ALPINE trial.

The overall safety profile of BRUKINSA in the ALPINE and SEQUOIA trials was consistent with prior studies. In the pooled safety population of CLL patients who received BRUKINSA across the clinical development program (N=1,550), the most common adverse reactions (=30%), were decreased neutrophil count (42%), upper respiratory tract infection (39%), decreased platelet count (34%), hemorrhage (30%), and musculoskeletal pain (30%). The pre-defined final PFS analysis of the ALPINE study demonstrating superior efficacy and a favorable cardiac safety profile for BRUKINSA versus IMBRUVICA in patients with R/R CLL, was presented in a late-breaking session at the 64th Annual American Society for Hematology (ASH) Meeting and published simultaneously in The New England Journal of Medicine.

With a median follow-up of 29.6 months, BRUKINSA demonstrated superior PFS compared with ibrutinib in patients with R/R CLL (HR: 0.65 [95% CI, 0.49-0.86] P=0.0024, for both investigator and IRC). Additionally, BRUKINSA demonstrated a favorable cardiac safety profile, with significantly lower rates of atrial fibrillation/flutter (5.2% vs 13.3%) and zero deaths due to cardiac disorders with BRUKINSA vs. six with ibrutinib (0% vs 1.9%).

ALPINE is a randomized, global Phase 3 trial (NCT03734016) comparing BRUKINSA against ibrutinib in previously treated patients with relapsed or refractory chronic lymphocytic leukemia CLL or SLL. In the trial, a total of 652 patients across Europe (60%), the United States (17%), China (14%), and New Zealand and Australia (9%) were randomized into two arms, with the first arm receiving BRUKINSA (160 mg orally twice daily) and the second arm receiving ibrutinib (420 mg orally once daily) until disease progression or unacceptable toxicity. The primary endpoint of ORR, defined by pre-specified non-inferiority of BRUKINSA versus ibrutinib, was assessed by investigator and IRC using the modified 2008 iwCLL guidelines, with modification for treatment-related lymphocytosis for patients with CLL, and per Lugano Classification for non-Hodgkin's lymphoma for patients with SLL.

There was pre-specified hierarchical testing of non-inferiority followed by superiority in ORR as assessed by investigator and IRC. Key secondary endpoints include PFS and event rate of atrial fibrillation or flutter; other secondary endpoints include duration of response, overall survival, and incidence of adverse events. Interim study results from ALPINE were published online in the Journal of Clinical Oncology in November 2022 and the final pre-defined PFS analysis was presented in a late-breaking session at the 64th Annual American Society for Hematology (ASH) Meeting and published simultaneously in The New England Journal of Medicine.

SEQUOIA is a randomized, multicenter, global Phase 3 trial (NCT03336333) designed to evaluate the efficacy and safety of BRUKINSA compared to bendamustine + rituximab (B+R) in patients with treatment-naïve CLL or SLL. The trial consists of three cohorts: Cohort 1 (n=479): randomized 1:1 to receive BRUKINSA (n=241) or B+R (n=238) until disease progression or unacceptable toxicity, in patients not harboring del(17p); data from this group comprise the primary endpoint; Cohort 2 (n=110): patients with del(17p) receiving BRUKINSA as a monotherapy; and Cohort 3 (enrollment ongoing): patients with del(17p) or pathogenic TP53 variant receiving BRUKINSA in combination with venetoclax. Patients with del(17p) were not randomized to Cohort 1, as they experience poor clinical outcomes and poor response to chemoimmunotherapy.

The primary endpoint of the trial is IRC-assessed PFS. Secondary endpoints include investigator-assessed PFS, IRC- and investigator-assessed ORR, overall survival, PFS and ORR in patients with del(17p), and safety. Results for Cohort 2 (Arm C), representing high-risk patients treated with BRUKINSA monotherapy, were presented at the 62nd ASH Annual Meeting in December 2020.

This cohort of patients with del(17p) achieved significant efficacy, with an 18-month PFS of 90.6%, as assessed by investigator. Full study results were published in Lancet Oncology.