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Zanubrutinib Outperforms Ibrutinib in Relapsed or Refractory CLL/SLL

January 2023, Vol 13, No 1

A head-to-head phase 3 clinical trial in patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) has found that zanubrutinib (Brukinsa), a next-generation Bruton tyrosine kinase (BTK) inhibitor, was more effective at preventing disease progression and is better tolerated than ibrutinib (Imbruvica), a first-generation BTK inhibitor that is the current standard of care for this population of patients.

The phase 3 ALPINE randomized trial had previously shown that zanubrutinib resulted in a superior overall response rate versus ibrutinib. The new ALPINE results, which were presented at a late-breaking session during the 64th American Society of Hematology Annual Meeting and Exposition and published simultaneously in the New England Journal of Medicine, showed that patients treated with zanubrutinib had a longer progression-free survival (PFS) at 29.6 months’ follow-up.

At 2 years, the PFS rate was 79.5% for zanubrutinib versus 67.3% for ibrutinib, for a 35% reduction in the risk for disease progression or death. The difference between the 2 treatment arms was particularly noteworthy in high-risk patients—those whose cancer harbors 17p deletion and/or TP53 mutations. In this group, the 2-year PFS rates were 77.6% for zanubrutinib and 55.7% for ibrutinib, for a 48% reduction in the risk for disease progression or death.

“Zanubrutinib not only improves the response rate, it also improves progression-free survival compared to ibrutinib, including in our highest risk patients,” said Jennifer R. Brown, MD, PhD, Director, Chronic Lymphocytic Leukemia Center, Dana-Farber Cancer Institute, Boston, MA, and Worthington and Margaret Collette Professor of Medicine, Hematologic Oncology, Harvard Medical School, Boston, who presented the results at the meeting.

“Progression-free survival is pretty much our gold standard for efficacy, so our data suggest that zanubrutinib should really become the new standard of care in this setting.”

Zanubrutinib is approved for use in patients with Waldenström macroglobulinemia, relapsed or refractory mantle-cell lymphoma, and marginal zone lymphoma. Approval for use in patients with CLL is currently under consideration by the FDA. Ibrutinib, the current standard of care, was the first BTK inhibitor to receive FDA approval. However, over time, it became evident that this drug was associated with significant side effects, including heart rhythm disorders.

“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.”

Study Details

The phase 3 ALPINE trial enrolled 652 patients with relapsed or refractory CLL/SLL and randomized them in a 1:1 ratio to receive zanubrutinib (N = 327) or ibrutinib (N = 325). Demographics and disease characteristics were well balanced between the arms. Treatment was continued until disease progression or unacceptable toxicity.

At a median follow-up of approximately 2.5 years, both PFS and overall response rates were significantly higher in the zanubrutinib arm versus the ibrutinib arm. This pattern was consistent across all major prespecified subgroups.

More importantly, patients in the zanubrutinib arm experienced fewer adverse events that led to drug discontinuation, dose reduction, or dose interruption. Fatal cardiac events occurred in 6 patients treated with ibrutinib versus none treated with zanubrutinib.

In the future, Dr Brown and her colleagues plan to track outcomes and analyze trends among patient subgroups, including those with 17p deletion, TP53, complex karyotype, and other mutations. Additional studies are planned to assess the use of zanubrutinib in combination with other therapies in CLL/SLL.

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