Zanubrutinib Shown Noninferior to Ibrutinib for Patients With R/R CLL/SLL

The use of zanubrutinib (Brukinsa) was found to be noninferior to treatment with ibrutinib (Imbruvica) for adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), meeting the primary end point of the phase 3 ALPINE trial (NCT03734016).

“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. Data from this interim analysis, in addition to Brukinsa’s comprehensive clinical program, provide important new information to support its benefit-risk profile,” Jane Huang, MD, chief medical officer, hematology, BeiGene, said in a statement.

According to data reported in a press release from the developer of zanubrutinib, BeiGene, the P-value for the objective response rate (ORR) comparison between zanubrutinib and ibrutinib was (P < .0001), according to both the investigator and independent review committee (IRC) assessments. The ORR was also statistically improved with zanubrutinib compared with ibrutinib by the investigator’s assessment (P = .0006) as well as the IRC (P = .0121). The results observed with zanubrutinib were also better compared to the responses observed during the interim analysis (P < .0099). The progression-free survival (PFS) data were immature at the time of data cutoff.

The safety end point, which was the key secondary end point of the ALPINE study, was also met during the interim analysis. BeiGene reported that zanubrutinib led to a statistically significant lower incidence of atrial fibrillation or flutter. Overall, the safety profile observed with the agent appeared to be consistent with what was reported earlier in its clinical development.

ALPINE is an ongoing global and randomized trial of 600 patients with relapsed or refractory CLL or SLL. The study is assessing ORR as its primary end point, along with secondary end points of the duration of response, time to response, overall survival, patient-reported outcomes, the incidence of adverse events, and rate of partial response with lymphocytosis or higher determined by IRC.

Patients with CLL or SLL who met the 2008 International Workgroup on CLL criteria, and who are relapsed or refractory to at least 1 prior line of therapy were eligible to enroll. Patients were also required to have measurable disease on CT or MRI, an ECOG performance status of 0 to 2, a life expectancy of 6 months or more, as well as adequate bone marrow, renal, and hepatic function.

The study excludes individuals with prolymphocytic leukemia or history of, current, or suspected Richter's transformation, major surgery within 4 weeks of the first dose of zanubrutinib, prior treatment with a Bruton’s tyrosine kinase inhibitor, toxicity from prior anticancer therapy that has been resolved to a grade ≤1 toxicity, were vaccinated with a live vaccine within 35 days of being dosed in the study, have hypersensitivity to either zanubrutinib or ibrutinib, or have comorbidities that may interfere with treatment. 

The ALPINE study is not the first stint for zanubrutinib as treatment of CLL and SLL. The agent was previously explored in the SEQUOIA trial (NCT03734016) and showed high ORRs in both CLL and SLL. Outside of these patient populations, zanubrutinib has shown promise as treatment of Waldenstrom macroglobulinemia (WM), and a new drug application was recently submitted to the FDA for a potential WM indication.

_Reference:

_{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/3gIcWK1}