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Zanubrutinib Better Than Ibrutinib in CLL/SLL?

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Zanubrutinib (Brukinsa), a second-generation Bruton tyrosine kinase (BTK) inhibitor, has shown a significantly greater delay in disease progression vs the standard of care ibrutinib (Imbruvica) in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), with equally encouraging reductions in adverse events.

The findings come from a preplanned interim analysis of the global, phase 3 ALPINE trial and were presented at the European Hematology Association 2021 annual meeting.

“These data support that more selective BTK inhibition, with more complete and sustained BTK occupancy, results in improved efficacy and safety outcomes,” said investigator Peter Hillmen, MD, professor of experimental hematology at the University of Leeds, UK.

“Zanubrutinib may minimize toxicities related to ibrutinib off-target inhibition, and zanubrutinib may improve efficacy outcomes,” he said.

The new results bode well for the drug gaining approval for use in CLL/SLL. At present, it is approved only for use in mantle cell lymphoma in patients who have received at least one prior therapy.

Better Efficacy, Fewer ADRs

In the trial, the patients with relapsed or recurrent CLL or SLL were treated either with zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily until disease progression.

The interim analysis was conducted on data available for 415 of the 652 patients enrolled.

For the primary endpoint of an overall response rate (ORR), at a median follow-up of 15 months, the rate was significantly higher among those treated with zanubrutinib vs ibrutinib (78.3% vs 62.5%; P = .0006).

When including the partial response with lymphocytosis, the ORR was 88.4% with zanubrutinib vs 81.3% with ibrutinib.

Importantly, among patients with the del(17p) mutation, which is associated with reduced survival and resistance to chemoimmunotherapy, those who were treated with zanubrutinib (n = 24) also had a significantly greater ORR (83.3%) than those with the mutation treated with ibrutinib (n = 26; ORR 53.8%).

Rates of progression-free survival among the zanubrutinib vs ibrutinib patients overall, in terms of 12-month event-free rates, were 94.9% vs 84%, respectively (HR, 0.40; P = .0007).

Results at an 18-month cut-off showed only 20 patients with progressive disease in the zanubrutinib group vs 42 in the ibrutinib group.

Overall survival rates were not statistically different, at 97% and 92.7%, at 12 months respectively (P = .1081).

In addition, zanubrutinib-treated patients had a substantially lower rate of atrial fibrillation/flutter, a known side effect of BTK inhibitors and pre-specified safety endpoint (2.5% vs 10.1%, 2-sided P = .0014).

Furthermore, rates of cardiac disorders of any grade were 13.7% with zanubrutinib vs 25.1% with ibrutinib, and those of grade 3 or higher were 2.5% and 6.8%, respectively.

Although the first-generation BTK inhibitor ibrutinib also has high response rates with CLL and SLL, treatment discontinuation is a significant problem, with as high as 25% to 30%, largely the result of toxicities from the BTK inhibitor drug, Hillmen commented.  

Zanubrutinib is designed to minimize toxicities with an increased specificity that reduces off-target inhibition of TEC and EGFR-family kinases, he explained.

The rate of major bleeding was lower with zanubrutinib (2.9% vs 3.9%), as were adverse events leading to discontinuation (7.8% vs 13%, respectively) or death (3.9% vs 5.8%).

Neutropenia was higher with zanubrutinib (28.4% vs 21.7%); however, grade 3 or higher infections were lower with the drug vs ibrutinib (12.7% vs 17.9%).

“The findings suggest neutropenia is a manageable complication with zanubrutinib,” Hillmen said.

Approached for comment on this study, EHA president John G. Gribben, DSc, director of the Experimental Cancer Medicine Centre, University of London, UK, said that longer-term results will help paint a fuller picture of zanubrutinib’s benefits.

“This was a preliminary evaluation of the data and the follow-up is still quite short. We will need to see further follow-up on this study to determine if the results hold up,” he told Medscape Medical News.

Gribben pointed out similar recent head-to-head research comparing acalabrutinib (Calquence), also a second-generation BTK inhibitor, to ibrutinib. 

“Although we always advise caution in doing side-by-side comparisons, investigators will be looking at these two trials together to assess the three different approved BTK inhibitors in these relapsed CLL patients,” he said.

Hillmen agreed that “we need to see more maturity in [the ALPINE study] to compare with the other trials,” but he noted that “both trials indicate that the tolerability of the second-generation BTK inhibitors in terms of cardiac toxicities is improved.”

The study was sponsored by BeiGene. Hillmen has received honoraria from BeiGene, Janssen, AbbVie, AstraZeneca, Roche, and others. Gribben has declared relationships with Janssen, Celgene, Bristol-Myers Squibb, AstraZeneca, AbbVie, Roche, Genentech, and Acerta Pharma.

European Hematology Association (EHA) 2021 Annual Meeting: Abstract LB1900. Presented June 11, 2021.

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