Zanubrutinib Emerges as Potential First-Line Therapy in Patients with High-Risk CLL/SLL

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Zanubrutinib shows potential in treating patients with treatment-naïve high-risk chronic lymphocytic leukemia and/or small lymphocytic lymphoma with del(17p) and/or TP53 mutation.

Zanubrutinib (Brukinsa; BeiGene Ltd) used in combination with venetoclax (Venclexta; Genentech) revealed significantly positive overall response rate (ORR) and complete response (CR) rates in treatment of patients with treatment-naïve (TN) high-risk chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with del(17p) and/or TP53 mutation. The findings, to be presented at the European Hematology Association 2024 Hybrid Congress, demonstrate the safety, efficacy, and tolerability of zanubrutinib in combination with BCL2 inhibitors for high-risk patients with CLL/SLL.

Destruction of lymphoblasts. Conceptual 3D illustration of treatment of acute lymphoblastic leukemia

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CLL/SLL is the most common adult leukemia affecting western populations, making up about 25% to 30% of cases in the United States. It is amonoclonal lymphoproliferative disease characterized by the accumulation and proliferation of mature but dysfunctional B lymphocytes. Currently, there is little understanding of the genetic or environmental mechanisms that underscore development of CLL/SLL, although some risk factors, such as exposure to certain chemicals, have been identified.1

Initial treatment options for patients with CLL/SLL and del(17p) and/or TP53 mutation include chemoimmunotherapy treatments such as single-agent ibrutinib (Imbruvica; Imbruvica), imbrutinib plus rituximab (Rituxan; Roche), single-agent venetoclax, and venetoclax plus obinutuzumab (Gazyva; Genentech). However, patients with mutations are often at high risk of not responding to treatment or relapsing shortly after.1

The recent randomized, multicenter, global SEQUOIA (NCT03336333) phase 3 trial investigated use of zanubrutinib, a small molecule inhibitor of Bruton’s tyrosine kinase (BTK) designed to inhibit the proliferation of malignant B cells by delivering sustained inhibition of the BTK protein, in patients with CLL/SLL and del(17p) and/or TP53 mutations. Compared with other available BTK inhibitors, zanubrutinib appears to have greater specificity and better bioavailability, potentially optimizing treatment outcomes and minimizing adverse effects for patients.2,3

The study involved 590 patients randomized into 3 cohorts: (1) treatment with zanubrutinib (n=241) or bendamustine (Bendeka; Eagle Pharmaceuticals Inc) plus rituximab (n=238) until disease progression or unacceptable toxicity; (2) treatment with single agent zanubrutinib until unacceptable toxicity or disease progression (n=110); and (3) treatment with zanubrutinib in combination with venetoclax (n=66).1,3

The study authors centrally assessed the third cohort of 66 patients with del(17p) and/or TP53 mutations who received zanubrutinib 160 mg 2 times daily for 3 months, followed by zanubrutinib at the same dose and venetoclax with a ramp-up dosing to 400 mg once daily for 12 to 24 cycles until progressive disease, unacceptable toxicity, or confirmed undetectable minimal residual disease (MRD). They noted significant successes in ORR, CR, minimal residual disease (MRD), and progression-free survival (PFS) amongst the assessed population.1,3

The results showed that in the 65 response-evaluable patients, ORR was 100%. Additionally, the rate of CR with incomplete hematopoietic recovery (CRi) was 48% (CR=46%; CRi=2%). Undetectable MRD was achieved in 59% of patients and median PFS was not reached; 12- and 24-month PFS estimates were 95% and 94%, respectively. The study authors cited no new safety concerns, although they did observe that 97% of patients experienced ≥1 treatment emergent adverse effect (TEAE), including all-grade non-hematologic TEAEs, and 44% experienced grade ≥3 non-hematologic TEAEs.1,3

The study findings demonstrate significant implications for improved ORR, CR, MRD, and PFS for patients with CLL/SLL, paving the way for future investigations into optimizing treatment strategies. Further investigations into use of zanubrutinib and BTK inhibitors emphasizes the importance of personalized medicine approaches to improve outcomes and quality of life for patients facing this challenging disease. As these therapies continue to evolve, ongoing research will be crucial in further refining treatment protocols and expanding therapeutic options for patients.

“SEQUOIA has shown that [zanubrutinib] is a highly effective monotherapy treatment for TN CLL patients, including those with high-risk markers like del(17p) and/or TP53 mutation. With one of the largest pools of high-risk patients of any published study to date, SEQUOIA arm D demonstrates how BCL2 inhibitor therapies can complement BRUKINSA as a backbone therapy to achieve deep clinical response even in this patient population,” Mehrdad Mobasher, MD, MPH, chief medical officer, Hematology at BeiGene, said in a press release. “We look forward to evaluating the potential for time-limited therapy with longer follow-up and incorporating these findings into our development program for our investigational next-generation BCL2 inhibitor sonrotoclax.”

References
1. Mukkamalla SKR, Taneja A, Malipeddi D, et al. Chronic Lymphocytic Leukemia. National Library of Medicine. March 7, 2023. Accessed June14, 2024. https://www.ncbi.nlm.nih.gov/books/NBK470433/
2. Tam C.S., Muñoz J.L., Seymour J.F. et al. Zanubrutinib: past, present, and future. Blood Cancer J. September 11, 2023. doi: 10.1038/s41408-023-00902-x
3. BeiGene to present new data from SEQUOIA study evaluating BRUKINSA® plus venetoclax in high-risk first-line CLL/SLL at EHA2024. Beigene. June 14, 2024. Accessed June 14, 2024. https://ir.beigene.com/news/beigene-to-present-new-data-from-sequoia-study-evaluating-brukinsa-plus-venetoclax-in-high-risk-first-line/03179dde-1bf5-4370-a9a1-74e1a17e0ee4/
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