Is Zanubrutinib Poised to Become a New Standard of Care in Relapsed or Refractory CLL and SLL?

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The next-generation Bruton’s tyrosine kinase (BTK) inhibitor zanubrutinib demonstrated superior progression-free survival compared with ibrutinib, with an improved cardiac safety profile, in the first head-to-head comparison between these two BTK inhibitors in relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). These results are from the randomized phase III ALPINE trial, presented at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition.1 Of note, zanubrutinib also improved progression-free survival in a subgroup of patients with high-risk disease—those with del(17p) and/or TP53 mutations.

At 2 years, progression-free survival rate was 79.5% with zanubrutinib vs 67.3% with ibrutinib (P = .0024), reflecting a 35% reduction in the risk for disease progression or death favoring zanubrutinib. In the group of patients at highest risk (ie, those with del(17p) and/or TP53 mutations), the 2-year progression-free survival rate was 77.6% with zanubrutinib vs 55.7% with ibrutinib (P = .0134), for a 48% reduction in the risk for disease progression or death favoring zanubrutinib.

“Zanubrutinib not only improves the response rate, but it also achieves superior progression-free survival compared with ibrutinib in relapsed or refractory CLL/SLL, including in our patients at highest risk,” said Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute and Harvard University.

Jennifer R. Brown, MD, PhD

Jennifer R. Brown, MD, PhD

“All major subgroups had improved progression-free survival with zanubrutinib, and zanubrutinib has a more favorable safety profile compared with ibrutinib. The cardiac safety profile included lower rates of adverse events, serious cardiac events, and cardiac events leading to treatment discontinuation,” Dr. Brown said. “Progression-free survival is pretty much our gold standard for efficacy, and with improved safety, our data suggest that zanubrutinib should become the standard of care in this setting.”

ALPINE is the first study to demonstrate superior progression-free survival in CLL or SLL in a head-to-head comparison of BTK inhibitors (ibrutinib vs zanubrutinib). The findings were published in The New England Journal of Medicine2 to coincide with Dr. Brown’s presentation at the ASH meeting.

CLL/SLL generally has an indolent course, but patients often relapse, and the disease is typically characterized by consecutive relapses on therapy. More effective therapies are needed to treat relapsing patients. About 25% of patients with relapsed or refractory CLL/SLL have del(17p)/TP53 mutations, which are associated with a poor prognosis.

Zanubrutinib has been approved by the U.S. Food and Drug Administration (FDA) in the treatment of several other types of cancer, including marginal zone lymphoma, mantle cell lymphoma, and Waldenström’s macroglobulinemia. Ibrutinib, currently a standard therapy for CLL/SLL, was the first BTK inhibitor to gain FDA approval and, at the time, was hailed as a major advance. The downside of ibrutinib is that it can cause significant side effects, including cardiac effects such as atrial fibrillation and hypertension, which have led to treatment discontinuation in 16% to 23% of patients, Dr. Brown noted. Zanubrutinib has greater BTK specificity than ibrutinib and is expected to achieve more sustained and complete BTK inhibition.

“The BTK inhibitor drug class has been transformative for CLL therapy, but the first-in-class drug ibrutinib has been somewhat difficult 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.” In another trial, zanubrutinib was superior to bendamustine plus rituximab in the first-line treatment of CLL, leading to longer progression-free survival in that setting (P < .0001).3

Study Details and Results

The ALPINE study was conducted across 15 countries and enrolled 652 patients with relapsed or refractory CLL/SLL. Patients were randomly assigned 1:1 to receive ­zanubrutinib at 160 mg twice daily (n = 327) or ibrutinib at 420 mg/d (n = 325). Treatment was continued until disease progression or unacceptable toxicity. Patients were stratified according to age, geographic location, disease refractoriness, and presence of del(17p)/TP53 mutation. The primary endpoint was objective response rate. Dr. Brown presented results for the key secondary endpoint of progression-free survival.

After enrollment, three patients in the zanubrutinib group and one patient in the ibrutinib group were never treated. Treatment is ongoing in 73% and 58% of patients in the zanubrutinib and ibrutinib groups, respectively.

At a median follow-up of 29.6 months, the 24-month landmark estimate of progression-free survival by independent review was 79% with zanubrutinib vs 67% with ibrutinib. In the group of patients at highest risk (ie, those with del[17p]/and or TP53 mutation), the 2-year progression-survival rate was 77.6% with zanubrutinib vs 55% with ibrutinib. The median treatment duration was 28.3 months with zanubrutinib vs 24.3 months with ibrutinib. 

Safety Profile

“The rate of all adverse events was lower with zanubrutinib compared with ibrutinib, and there were fewer dose interruptions,” Dr. Brown said. Serious cardiac adverse events were reported in 1.9% of the zanubrutinib-treated group vs 7.7% of those who received ibrutinib. The number of cardiac events leading to treatment discontinuation was 1 vs 14, respectively. Atrial fibrillation was reported in 5% vs 13%, respectively. No fatal cardiac events were reported in the zanubrutinib-treated group vs six in the ibrutinib-
treated group.

Clinical Implications

During the discussion following the presentation of these data at a press conference, Dr. Brown was asked whether there is still a role for ibrutinib in CLL. “I am not aware of a patient population for whom I would select ibrutinib over zanubrutinib. This is reflected in the most recent NCCN Guidelines® [National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology], where zanubrutinib is listed as a ‘preferred’ drug in CLL,” she said.

“In general, you can’t use another covalent inhibitor after a different covalent inhibitor. However, if a person had an adverse event on ibrutinib, that person could be switched to zanubrutinib, because as we saw, there is less toxicity,” she added. 

DISCLOSURE: The trial was funded by BeiGene, the developer of zanubrutinib. Dr. Brown has served as a consultant to AbbVie, Acerta/AstraZeneca, BeiGene, Bristol Myers Squibb/Juno/Celgene, Catapult, Genentech/Roche, Janssen, MEI Pharma, MorphoSys AG, Novartis, Pfizer, Rigel, Grifols Worldwide Operations, Hutchmed, iOnctura, and Pharmacyclics; and has received research funding from BeiGene, MEI Pharma, Gilead Sciences, Loxo/Lilly, Verastem/SecuraBio, TG Therapeutics, and iOnctura.


1. Brown JR, Eichhorst B, Hillmen P, et al: Zanubrutinib demonstrates superior progression-free survival compared with ibrutinib for treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: Results from final analysis of ALPINE randomized phase 3 study 2022 ASH Annual Meeting and Exposition. Abstract LBA-6. Presented December 13, 2022.

2. Brown JR, Eichhorst B, Hillmen P, et al: Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. December 13, 2022 (early release online).

3. Tam CS, Brown JR, Kahl BS, et al: Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): A randomised, controlled, phase 3 trial. Lancet Oncol 23:1031-1043, 2022.

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