Zanubrutinib, a second-generation Bruton’s tyrosine kinase (BTK) inhibitor, significantly improved response rates and delayed disease progression as compared with the standard of care, ibrutinib, in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL), and did so with less toxicity, in an interim analysis of the global phase III ALPINE trial reported at the European Hematology Association (EHA) 2021 Virtual Congress.¹

“In this interim analysis, zanubrutinib, compared with ibrutinib, was shown to have a superior response rate, improved progression-free survival, and a lower rate of atrial fibrillation or flutter,” said Peter Hillmen, MBChB, PhD, Professor of Experimental Hematology at the University of Leeds in the United Kingdom.

Peter Hillmen, MBChB, PhD

“These data support the concept that more selective BTK inhibition, with more complete and sustained BTK occupancy, results in improved efficacy and safety outcomes.”

Zanubrutinib is currently approved in the United States for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy.

Study Details

In the ALPINE trial, 652 patients with relapsed or recurrent CLL/SLL were treated with either zanubrutinib at 160 mg twice daily or ibrutinib at 420 mg once daily until disease progression. Approximately 20% of patients had a del(17p) and/or TP53 mutation. Fewer than 15% of patients were on anticoagulants.

The interim analysis was conducted on data available for the first 12 months after the random assignment of 415 patients. Median follow-up was 15 months.

The primary endpoint of overall response rate by investigator assessment was significantly higher in the zanubrutinib arm vs ibrutinib arm (78.3% vs 62.5%; P = .0006). When the analysis included patients with lymphocytosis (who by design were not included in the primary endpoint analysis), the response rate was 88.4% vs 81.3%, respectively. 

Importantly, for the poor-prognosis subset of 50 patients with del(17p) mutations, treatment with zanubrutinib significantly increased response rates as well—83.3% vs 53.8%, Dr. Hillmen reported. He added that throughout the key patient subgroups, zanubrutinib was favored.

“Zanubrutinib was also superior to ibrutinib in terms of progression-free survival,” he further reported. The 12-month landmark event-free rates for zanubrutinib vs ibrutinib were 94.9% vs 84.0%, respectively (HR = 0.40; P = .0007). “And if we look at patients with aggressive disease, at 18 months, 20 patients had disease progression on zanubrutinib compared to 42 patients with ibrutinib,” he said.

At 12 months, overall survival (which was not a prespecified analysis) was not statistically different, at 97.0% with zanubrutinib and 92.7% with ibrutinib (HR = 0.54; P = .1081), reflecting 11 and 19 deaths, respectively.

Zanubrutinib More Tolerable

Results confirmed that this second-generation BTK inhibitor may be far more tolerable than the older agent. Zanubrutinib was designed to minimize toxicities with an increased specificity that reduces off-target inhibition of TEC and EGFR family kinases. Although ibrutinib yields high response rates in CLL and SLL, treatment discontinuation rates can be as high as 30%, primarily due to toxicities associated with the first-generation agent, Dr. Hillmen said.

Approximately half the patients in each arm experienced grade ≥ 3 adverse events, 55.9% with zanubrutinib and 51.2% with ibrutinib. Encouragingly, a substantially lower rate of atrial fibrillation/flutter, a known side effect of BTK inhibitors and a key secondary endpoint, was observed with zanubrutinib (2.5% vs 10.1%; P = .0014), and rates of cardiac disorders of any grade were lower (13.7% vs 25.1%), as were those of grade ≥ 3 cardiac disorders (2.5% and 6.8%), he reported.

Major bleeding rates were also lower with zanubrutinib (2.9% vs 3.9%), as were adverse events leading to treatment discontinuation (7.8% vs 13.0%, respectively) or death (3.9% vs 5.8%). With ibrutinib, there were slightly more reports of arthralgia (14.0% vs 9.3%) and muscle spasm (11.1% vs 2.9%). In contrast, neutropenia occurred more often with zanubrutinib (28.4% vs 21.7%), “but this did not translate into a high rate of infections…. This is a manageable complication,” he said.

What About Acalabrutinib?

In the discussion period, Dr. Hillmen was asked to compare the results of ALPINE with those of ELEVATE-RR, which compared acalabrutinib with ibrutinib and demonstrated a noninferior progression-free survival and significantly less atrial fibrillation.² Those results were presented recently at the ASCO Annual Meeting, and Dr. Hillmen was a co-investigator. His response was that these two second-generation BTK inhibitors “are not exactly the same,” in that they have different specificities and off-target inhibitions that can impact toxicity and perhaps “even efficacy,” he said.

In addition, ELEVATE-RR selected for del(17p) or del(11q) patients, whereas ALPINE enrolled all-comers with relapsed CLL. Perhaps most importantly, he added, data from ELEVATE-RR are based on 3 years of treatment, compared with the much shorter timeline for ALPINE. “We need to see more maturity in this ­[ALPINE] trial to really compare,” he said.

Dr. Hillmen added that one conclusion is common to both trials and has become apparent: the tolerability of the second-generation BTK inhibitors is better than that of their first-generation counterpart. 

DISCLOSURE: The study was sponsored by BeiGene. Dr. Hillmen has received honoraria from AbbVie, Janssen, and Roche; has received institutional research funding from AbbVie, Gilead Sciences, Janssen, Pharmacyclics, and Roche; and has been reimbursed for travel, accommodations, or other expenses by AbbVie and Janssen.

REFERENCES

1. Hillmen P, Eichhorst B, Brown JR, et al: First interim analysis of ALPINE study: Results of a phase 3 randomized study of zanubrutinib vs ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. EHA 2021 Virtual Congress. Abstract LB1900. Presented June 11, 2021.  

2. Byrd JC, Hillmen P, Ghia P, et al: First results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia. 2021 ASCO Annual Meeting. Abstract 7500. Presented June 4, 2021.