Zanubrutinib Improves ORR for CLL/SLL Over Ibrutinib in Phase III ALPINE Study 

Take-aways:  

• Zanubrutinib led to a significantly higher ORR than ibrutinib in patients with relapsed or refractory CLL/SLL in an interim analysis of the phase III ALPINE trial. 
• Zanubrutinib had an improved cardiac safety profile compared with ibrutinib. 
• The increased BTK occupancy and specificity of zanubrutinib may improve its efficacy and reduce off-target toxicities. 

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Zanubrutinib led to a significantly higher overall response rate (ORR) than ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL), according to an interim analysis of the phase III ALPINE study. 

Peter Hillmen, MBChB, PhD, of St. James’s University Hospital in the United Kingdom, and colleagues conducted the global, multicenter, open-label, head-to-head study and published its results in the Journal of Clinical Oncology.  

Ibrutinib, a first-generation Bruton’s tyrosine kinase (BTK) inhibitor, is a standard treatment option for patients with untreated, relapsed, or refractory CLL. However, it is associated with adverse events that “may be attributed to off-target kinase inhibition,” and approximately one-fifth of patients discontinue ibrutinib because of treatment-related toxicities, Dr. Hillmen and colleagues wrote. 

Zanubrutinib, a potent, irreversible, next-generation BTK inhibitor, is “more selective” for BTK inhibition and “exhibits less off-target kinase activity” than ibrutinib, the study’s authors wrote, noting it is “hypothesized that higher selectivity reduces toxicities and high BTK occupancy maximizes efficacy, potentially increasing the likelihood of achieving deep and sustained remission in CLL.” 

Methods

The study included adults with a confirmed diagnosis of CLL or SLL who met International Workshop on CLL (iwCLL) criteria. All patients were relapsed or refractory after at least one prior line of therapy, had measurable disease by imaging, and had an Eastern Cooperative Oncology Group performance status score of two or less.  

The study’s investigators enrolled 652 patients from 113 sites across 15 countries from November 1, 2018, to December 14, 2020. The interim analysis included the first 415 patients enrolled in the study.  

The median patient age was 67 years (range, 35 to 90 years), 83% of patients were White, and 12% were Asian. Patients had a median of one prior line of therapy (range, one to eight lines), while 9% received more than three lines of therapy.  

They randomized patients 1:1 to receive zanubrutinib 160 mg twice daily (n=207) or ibrutinib 420 mg once daily (n=208) until progressive disease or unacceptable toxicity.  

The study’s primary efficacy endpoint was investigator-assessed ORR, which investigators defined as complete response or partial response (PR).  

The study’s secondary endpoints included progression-free survival (PFS), atrial fibrillation/flutter rate, duration of response, rate of PR with lymphocytosis or higher, overall survival (OS), time to treatment failure, and patient-reported outcomes.  

At the data cutoff on December 31, 2020, 87.4% of patients in the zanubrutinib arm were still receiving treatment, and 75.5% in the ibrutinib arm were still receiving treatment.  

Consistent Benefit in Favor of Zanubrutinib

The investigator-assessed ORR was significantly higher in the zanubrutinib arm (78.3%) than in the ibrutinib arm (62.5%; two-sided P<.001) at a median follow-up of 15.3 months. 

There was a “consistent benefit in favor of zanubrutinib” observed in all prespecified patient subgroups, Dr. Hillmen and colleagues wrote, noting zanubrutinib led to a higher ORR than ibrutinib in patients with del(17p)/TP53 mutation and in those with del(11q). 

The ORR as assessed by blinded independent central review met noninferiority, with a 76.3% ORR in the zanubrutinib arm and a 64.4% ORR in the ibrutinib arm (P<.001) but did not meet superiority (P=.0121). In patients with del(17p)/TP53 mutation, the ORR as assessed by blinded independent central review was 80.5% in the zanubrutinib arm and 55.3% in the ibrutinib arm. 

More than three-quarters of patients in each arm achieved a best overall response of PR with lymphocytosis or better, with most responders in each arm having a response that lasted at least 12 months. The 12-month PFS and OS rates, as assessed by investigators, were higher in the zanubrutinib arm (see TABLE 1).  

Nearly all patients in the study experienced at least one adverse event, with fatal adverse events occurring in eight patients who received zanubrutinib and in 12 patients who received ibrutinib. See TABLE 2 for details on adverse events.  

Infection events were the most common adverse events of interest that led to treatment discontinuation, occurring in 2.9% of patients in each arm.  

Atrial fibrillation/flutter of any grade occurred in 2.5% of patients in the zanubrutinib arm, significantly lower than the rate of 10.1% in the ibrutinib arm (two-sided P=.001).  

“Rates of cardiac events, major hemorrhages, and adverse events leading to treatment discontinuation or death were lower with zanubrutinib,” the study’s authors wrote. 

Results Favor Zanubrutinib

The interim analysis of the ALPINE study showed “superior ORR, improved PFS, and lower rates of atrial fibrillation/flutter in patients with relapsed or refractory CLL/SLL treated with zanubrutinib compared with ibrutinib,” Dr. Hillmen and colleagues concluded. “Initial data support the hypothesis that complete/sustained BTK occupancy may improve efficacy outcomes and increased specificity may minimize off-target inhibition-related toxicities.” 

However, they acknowledged the study has several limitations, noting that PFS and OS data “should be interpreted with caution” due to the “preliminary nature of the survival analysis.”  

The research was supported by BeiGene. Investigators and BeiGene collaborated on protocol development, data collection, and interpretation. BeiGene performed statistical analyses. 

Reference 

Hillmen P, Eichhorst B, Brown JR, et al. Zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: interim analysis of a randomized phase III trial. J Clin Oncol. 2023;41(5):1035-1045. doi:10.1200/JCO.22.00510