Results of the final progression free survival (PFS) analysis of the Phase 3 ALPINE trial (NCT03734016) comparing zanubrutinib (BGB-3111; Brukinsa®; BeiGene) with with ibrutinib (Imbruvica®; Pharmacyclics/Janssen Biotech) were presented during a late-breaking oral presentation session at the 64th American Society of Hematology (ASH) Annual Meeting held in New Orleans, December 10 – 13, 2022. [1] The data was simultaneously published online in The New England Journal of Medicine. [2]

Zanubrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK) that is currently being evaluated globally in a broad clinical program as a monotherapy and in combination with other therapies to treat various B-cell malignancies. The drug was specifically designed to deliver targeted and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity. With differentiated pharmacokinetics compared to other approved BTK inhibitors, zanubrutinib has been demonstrated to inhibit the proliferation of malignant B cells within a number of disease-relevant tissues.

Zanubrutinib has received US Food and Drug Administration (FDA) approval for treating several types of cancer.

Global phase 3 trial
The Phase 3 ALPINE study is a global trial comparing zanubrutinib with ibrutinib in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL).

CLL and SLL are cancers affecting lymphocytes, a type of white blood cell. While they are generally slow-growing cancers, they often recur after initial treatment, underscoring the continuing need for more effective therapies. Hence, there is an unmet need to develop an alternative treatment option.

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CLL accounts for about one-quarter of new cases of leukemiai The condition is characterized by consecutive relapses, with response to therapy ultimately determining clinical benefit, including survival.

Study design
The 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.

Final analysis
In this final PFS analysis, zanubrutinib achieved superior PFS compared with ibrutinib, as assessed by both Independent Review Committee (IRC) and investigator (HR: 0.65 [95% CI, 0.49-0.86] p =.0024, for both investigator and IRC). The PFS results favored zanubrutinib consistently across major pre-defined subgroups including IGHV status and patients with del(17p)/TP53, regardless of IRC or investigator assessment.

“Zanubrutinib is the only BTK inhibitor to demonstrate superior efficacy over ibrutinib in any treatment setting; The ALPINE trial results demonstrate superiority for both PFS and ORR versus ibrutinib in relapsed or refractory CLL/SLL,” noted Mehrdad Mobasher, M.D., M.P.H. Chief Medical Officer, Hematology at BeiGene.

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 is the Director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute and the Worthington and Margaret Collette Professor of Medicine in the Field of Hematologic Oncology at Harvard Medical School in Boston, Massachusetts. Her interests include the development of novel targeted therapeutics for CLL, as well as CLL genomics.

“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, 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,” Brown added.

At this pre-defined response analysis with a median follow up of 29.6 months, zanubrutinib was generally well-tolerated with a safety profile consistent with previous reports. Overall discontinuation rates were lower with zanubrutinib (26.3%) compared to ibrutinib (41.2%), as well as discontinuations due to adverse events (16.2 vs 22.8%) or progressive disease (7.3 vs 12.9%).

Cardiac safety
The current standard therapy for CLL and SLL, ibrutinib, was the first BTK inhibitor to gain FDA approval but can cause 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,” Brown said.

“We found that zanubrutinib caused fewer adverse events, and in particular much less cardiac toxicity,” she added.

In the analysis of the Phase 3 ALPINE trial cardiac safety measures favored zanubrutinib compared with ibrutinib: the rate of atrial fibrillation/flutter in the zanubrutinib arm remained low (5.2%) compared with ibrutinib (13.3%) and there were zero grade 5 adverse events due to cardiac disorders with zanubrutinib versus six in the ibrutinib arm.

“With nearly 30 months of follow up in this trial, we have seen a very consistent safety and tolerability profile for zanubrutinib and look forward to sharing detailed results from this analysis at ASH,” Mobasher concluded.

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.

Clinical trial
A Study of Zanubrutinib (BGB-3111) Versus Ibrutinib in Participants With Relapsed/Refractory Chronic Lymphocytic Leukemia (ALPINE) – NCT03734016

Highlights of prescribing information
Zanubrutinib (Brukinsa®; BeiGene) [Prescribing Information]
Ibrutinib (Imbruvica®; Pharmacyclics/Janssen Biotech) [Perscription Information]

[1] Brown JR,Eichhorst B, Hillmen P, Lamanna N, O’Brien SM, Tam CS, Qiu L, Kaźmierczak M, Jurczak W, et al. Zanubrutinib Demonstrates Superior Progression-Free Survival (PFS) Compared with Ibrutinib for Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (R/R CLL/SLL): Results from Final Analysis of ALPINE Randomized Phase 3 Study. Abstract: LBA-6 Late-Breaking Abstracts Session. Presented during the 64th American Society of Hematology (ASH) Annual Meeting held in New Orleans, December 10 – 13, 2022.
[2] Brown JR, Eichhorst B, Hillmen P, Jurczak W, Kaźmierczak M, Lamanna MN, et al. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. December 13, 2022 DOI: 10.1056/NEJMoa2211582

Featured image: American Society of Hematology’s (ASH) 64th Annual Meeting at the Ernest N. Morial Convention Center. Photo courtesy: © 2022 ASH/Matt Herp 2022. Used with permission.

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