Zanubrutinib Shows Noninferiority, Improved Safety Vs Ibrutinib in Relapsed/Refractory CLL

Jane Huang, MD

Zanubrutinib (Brukinsa) demonstrated noninferiority in objective response rates and a trend toward improved progression-free survival (PFS) when compared with ibrutinib (Imbruvica) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to results of a planned interim analysis of the ongoing phase 3 ALPINE study.¹

Data showed that zanubrutinib was noninferior in ORR when assessed by both investigator and an independent review committee (IRC; P <.0001). However, there was superiority in ORR by investigator assessment with zanubrutinib vs ibrutinib that was statistically significant (P = .0006), and also a numerically higher ORR with zanubrutinib by IRC that was not statistically significant (P = .0121). The latter P value was compared with the 2-sided stringent statistically boundary of P <.0099 set for the interim analysis.

The data are based on the 415 of 652 patients enrolled on the ALPINE study who have been followed for a minimum of 1 year. Progression-free survival (PFS), which is a secondary end point of the ALPINE study, were immature at the data cutoff for the interim analysis, but descriptive summaries showcased an early trend that favored zanubrutinib on the trial.

Regarding safety, zanubrutinib also demonstrated a statistically significant lower risk of atrial fibrillation or flutter compared with ibrutinib. The safety profile overall of zanubrutinib was consistent with that seen in prior studies.

“The interim results from this head-to-head trial demonstrated that, as a selective inhibitor designed to deliver sustained and continuous inhibition of BTK, Brukinsa provides CLL patients with improvements in response and reduced rates of atrial fibrillation or flutter compared to ibrutinib,” said Jane Huang, MD, chief medical officer, hematology of BeiGene, the developr of zanubrutinib. “Data from this interim analysis, in addition to Brukinsa’s comprehensive clinical program, provide important new information to support its benefit-risk profile.”

BeiGene also noted that it plans to consult with regulatory authorities regarding next steps with the ALPINE data, which are slated to be presented at an upcoming medical meeting.

In the international, phase 3 ALPINE trial (NCT03734016), investigators are evaluating 160 mg of oral zanubrutinib twice daily compared with at 420 mg of oral ibrutinib once daily in 652 previously treated patients with relapsed/refractory CLL or small lymphocytic lymphoma (SLL) until disease progression or unacceptable toxicity.²

In the primary analysis of ORR, which was defined by prespecified noninferiority of zanubrutinib bs ibrutinib, was evaluated by investigator and IRC through the modified 2008 International Working Group CLL guidelines with modification for treatment-related lymphocytosis for those with CLL and per Lugano Classification for non-Hodgkin lymphoma for those with SLL.

Hierarchical testing of noninferiority was followed by superiority in investigator- and IRC-assessed ORR.

Secondary end points included PFS, duration of response, overall survival, and incidence of adverse events. The prespecified end points of ORR and PFS will be evaluated at the planned final analysis of ALPINE, which is expected in 2022.

Zanubrutinib is currently approved for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least 1 prior therapy. Most recently, in February 2021, the FDA has accepted a supplemental NDA of zanubrutinib for the treatment of adult patients with Waldenström macroglobulinemia. The FDA’s action date for this application is October 18, 2021.

References

1. 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. News release. BeiGene. April 28, 2021. Accessed April 28, 2021. https://bit.ly/3u0LURD
2. Hillmen P, Brown JR, Byrd JC, et al. ALPINE: phase III zanubrutinib (BGB-3111) versus ibrutinib in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL). J Clin Oncol. 2019;37(suppl 15):TPS7572. doi: 10.1200/ JCO.2019.37.15_suppl.TPS7572.