Zanubrutinib—a second-generation Bruton's tyrosine kinase (BTK) inhibitor—significantly improved response rates and delayed disease progression as compared to 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. Data from the first interim analysis of the global phase III ALPINE trial were reported by Peter Hillmen, MBChB, PhD, and colleagues at the European Hematology Association 2021 Virtual Congress (LBA1900).

“These data support that more selective BTK inhibition, with more complete and sustained BTK occupancy, results in improved efficacy and safety outcomes,” said Dr. Hillmen, Professor of Experimental Hematology at the University of Leeds in the United Kingdom.

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

— Peter Hillmen, MBChB, PhD

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Zanubritinib is currently approved in the United States for use in mantle cell lymphoma in patients who have received at least one prior therapy.

More on the ALPINE Trial

In the trial, 652 patients with relapsed or refractory CLL or SLL were treated either with 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.

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 the ibrutinib arm (78.3% vs 62.5%; P = .0006). When the analysis included partial response with lymphocytosis, the overall 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 also significantly increased response rates—83.3% vs 53.8%, Dr. Hillmen reported.

The 12-month rates of progression-free survival for the zanubrutinib arm vs ibrutinib arm were 94.9% vs 84%, respectively (hazard ratio = 0.40, P = .0007). “And if we look at patients with aggressive disease, at the 18-month time point, 20 patients had progressed on zanubrutinib compared to 42 patients with ibrutinib,” he added.

Overall survival rates in this interim analysis were not statistically different—97.0% and 92.7% at 12 months, respectively (P = .1081).

Tolerability of Zanubrutinib

Zanubrutinib was designed to minimize toxicities with an increased specificity that reduces off-target inhibition of TEC and EGFR family kinases. While ibrutinib yields high response rates in CLL and SLL, treatment discontinuation rates can be as high as 30%, primarily due to toxicities associated with this first-generation agent, Dr. Hillmen said.

Approximately half of 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 prespecified safety endpoint, was observed with zanubrutinib (2.5% vs 10.1%, 2-sided P = .0014). Rates of cardiac disorders of any grade were lower (13.7% vs 25.1%), as were those grade ≥ 3 (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%) or death (3.9% vs 5.8%).

In contrast, neutropenia was reported more often in the zanubrutinib arm (28.4% vs 21.7%); however, grade ≥ 3 infections were less frequent vs ibrutinib (12.7% vs 17.9%).

“The findings suggest neutropenia is a manageable complication with zanubrutinib,” he offered.

Comparison to ELEVATE-RR

In the discussion period, Dr. Hillmen was asked to compare the results of ALPINE with those of ELEVATE-RR, which compared acalabrutinib and ibrutinib and demonstrated a noninferior progression-free survival and significantly less atrial fibrillation. Those results were presented recently at the ASCO Annual Meeting (Abstract 7500), 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-R/R was selective for del(17p) or del(11q) patients, while ALPINE enrolled all-comers with relapsed CLL, and ELEVATE-R/R has 3 years of data, compared to 15 months of interim findings for ALPINE, he said, adding, “We need to see more maturity in [the ALPINE] trial to really compare.”

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 counterparts.

Disclosure: For full disclosures of the study authors, visit library.ehaweb.org.