Zanubrutinib showed superior efficacy to ibrutinib—with fewer side effects—in the first head-to-head comparison between the Bruton’s tyrosine kinase (BTK) inhibitors among patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), according to data presented by Jennifer R. Brown, MD, PhD, and colleagues at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition (Abstract LBA-6). The findings were also simultaneously published in The New England Journal of Medicine.
CLL and SLL are cancers affecting lymphocytes. While they are generally slow-growing cancers, they often recur after initial treatment, underscoring the continuing need for more effective therapies.
At 2 years, 79% of patients taking zanubrutinib and 67% of those taking ibrutinib were still alive without evidence of their cancer returning. The study was conducted in patients whose CLL or SLL had not responded to an initial course of therapy or came back after an initial response. The results revealed a particularly dramatic difference in people whose CLL has del(17p) and/or TP53 mutations—mutations present in about one-quarter of relapsed CLL and SLL tumors that are associated with a poorer prognosis.
Jennifer R. Brown, MD, PhD
“Zanubrutinib not only improves the response rate, it also improves progression-free survival compared to ibrutinib, including in our highest-risk patients,” said Dr. Brown, of Dana-Farber Cancer Institute and Harvard University. “Progression-free survival is pretty much our gold standard for efficacy, so our data suggest that zanubrutinib should really become the standard of care in this setting.”
Zanubrutinib has received U.S. Food and Drug Administration (FDA) approval for treating several other types of cancer. Ibrutinib, currently a standard therapy for CLL and SLL, was the first BTK inhibitor to gain FDA approval—but it can cause significant side effects, including heart rhythm disorders. BTK inhibitors are given orally and work by interfering with a key signaling pathway in cancer cells.
“The BTK inhibitor drug class has been transformative for CLL therapy, but the first-in-class drug ibrutinib has been somewhat hard to tolerate for many patients, with cardiac side effects being one of the biggest problems,” said Dr. Brown. “We found that zanubrutinib caused fewer adverse events, and in particular, much less cardiac toxicity.”
ALPINE Trial
The phase III ALPINE trial enrolled 652 patients with relapsed or refractory CLL or SLL in 15 countries. Half of the participants received zanubrutinib and half received ibrutinib; patients continued taking their assigned treatment until their cancer grew worse or they experienced unacceptable side effects.
At a median follow-up of about 2.5 years, patients taking zanubrutinib had a significantly higher overall response rate and superior progression-free survival—a finding that held across all major predefined subgroups. Participants taking zanubrutinib also experienced fewer adverse events that led to drug discontinuation, dose reduction, or dose interruption. Fatal cardiac events occurred in six of the patients taking ibrutinib and none of those taking zanubrutinib.
The researchers will continue to track outcomes and analyze trends among patient subgroups, including those with del(17p), TP53, complex karyotype, and other mutations. Additional studies are planned to assess the use of zanubrutinib in combination with other therapies.
Disclosure: The trial was funded by BeiGene. For full disclosures of the study authors, visit ash.confex.com or nejm.org.
