Study Shows Zanubrutinib May Outperform Ibrutinib in Treatment of R/R CLL/SLL

Zanubrutinib (Brukinsa; BeiGene Ltd) demonstrated a sustained progression-free survival (PFS) and favorable tolerability over ibrutinib (Imbruvica; Janssen Biotech Inc), according to data from the randomized phase 3 ALPINE study (NCT03734016) comparing the overall response rate (ORR) of each agent in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL). The findings, published in Blood, suggest the superiority of zanubrutinib over ibrutinib, with zanubrutinib resulting in an ORR of over 85% at the average 42.5-month follow-up.^1,2

Zanabrutinib is a potent BTK inhibitor designed to bind to BTK proteins with greater precision for longer durations. Image Credit: © Nicat - stock.adobe.com

CLL/SLL is the most common low-grade B-cell leukemia diagnosed in the United States and Europe, affecting nearly 4.9 per 100,000 individuals per year. It is a slow-growing amonoclonal lymphoproliferative disease characterized by the growth and proliferation of mature but immunologically dysfunctional B lymphocytes located in the blood, spleen, lymph nodes, and bone marrow. The mechanism underlying development of CLL/SLL is unknown; however, studies suggest the potential influence of genetic or environmental factors, as well as exposure to certain chemicals.^3,4

Treatment options for CLL/SLL vary but typically involves chemoimmunotherapy or emerging targeted Bruton tyrosine kinase (BTK) inhibitors. Despite the success of these treatments, many patients continue to relapse or become refractory to certain agents. In multiple studies, zanubrutinib and ibrutinib have demonstrated statistically meaningful benefits for patients with CLL/SLL.^3,4

Ibrutinib is a BTK inhibitor approved by the FDA in 2014 and indicated for treatment of various B-cell malignancies. According to 10-year follow-up data from the RESONATE-2 trial (NCT01722487), ibrutinib demonstrated a median PFS of 8.9 years, demonstrating the drug as a well-tolerated and efficacious treatment. Although, trial data indicate zanubrutinib may be a more efficacious treatment for some patients without the challenging adverse effects associated with ibrutinib.^5,6

Zanabrutinib is a potent BTK inhibitor designed to bind to BTK proteins with greater precision for longer durations, as well as persist at high concentrations during treatment. In 2019, it was approved by the FDA for CLL/SLL based on results from the SEQUOIA trial (NCT03336333). In the ALPINE trial, researchers randomized treatment for 652 patients with R/R CLL/SLL who receive either zanubrutinib (n=327) or ibrutinib (n=325).^7,8

At a median follow-up of 42.5 months, PFS benefit with zanubrutinib compared with ibrutinib was sustained (HR: 0.68 [95% CI, 0.54-0.84]), including in patients with del(17p)/TP53 mutation (HR: 0.51 [95% CI, 0.33-0.78]) and across multiple sensitivity analyses. The ORR remained high in the zanubrutinib treatment arm versus ibrutinib (85.6% vs 75.4%) and deepened overtime, with incomplete bone marrow recovery rates of 11.6% (zanubrutinib) and 7.7% (ibrutinib). Although the overall survival end point has not been reached in each group, there were fewer mortalities in the patients receiving zanubrutinib compared with ibrutinib (HR: 0.77 [95% CI, 0.55-1.06]).²

The safety profile for zanabrutinib was favorable; however, both treatment arms experienced some adverse events including COVID-19-related infection (46.0% vs 33.3%), diarrhea (18.8% vs 25.6%), upper respiratory tract infection (29.3% vs 19.8%), and hypertension (27.2% vs 25.3%). The data shows that zanabrutinib demonstrates improved efficacy and overall safety compared with ibrutinib.²

The data support the success of zanabrutinib as a potent BTK therapy for treatment of patients with R/R CLL/SLL, offering therapeutic options with improved safety and tolerability. Clinical trials continue to study zanabrutinib as a monotherapy, as well as in combination with other agents.

REFERENCES

1. A study of zanubrutinib (bgb-3111) versus ibrutinib in participants with relapsed/​refractory chronic lymphocytic leukemia (alpine). ClinicalTrials.gov Identifier: NCT03734016. Updated April 1, 2024. Accessed October 1, 2024. https://clinicaltrials.gov/study/NCT03734016

2. Brown J, Eichhorst B, Lamanna N, et al. Sustained benefit of zanubrutinib vs ibrutinib in patients with r/r cll/sll: final comparative analysis of alpine. Blood. September 24, 2024. doi:10.1182/blood.2024024667

3. Zanubrutinib emerges as potential first-line therapy in patients with high-risk cll/sll. Pharmacy Times. June 14, 2024. Accessed October 1, 2024. https://www.pharmacytimes.com/view/zanubrutinib-emerges-as-potential-first-line-therapy-in-patients-with-high-risk-cll-sll

4. Long-term follow-up of ibrutinib in cll/sll: insights and outcomes. Pharmacy Times. July 1, 2024. Accessed October 1, 2024. https://www.pharmacytimes.com/view/long-term-follow-up-of-ibrutinib-in-cll-sll-insights-and-outcomes

5. Fda approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. FDA. January 19, 2023. Accessed October 1, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanubrutinib-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma

6. A study of ibrutinib in treatment naïve participants with chronic lymphocytic leukemia (cll) or small lymphocytic lymphoma (sll) (resonate-2).Clinicaltrials.gov Identifier: NCT01722487. Updated November 30, 2017. Accessed October 1, 2024. https://clinicaltrials.gov/ct2/show/NCT01722487

7. Zanubrutinib’s approval improves targeted treatment for cll. National Cancer Institute. January 27, 2023. Accessed October 1, 2024. https://www.cancer.gov/news-events/cancer-currents-blog/2023/fda-zanubrutinib-cll-sll

8. A study comparing zanubrutinib with bendamustine plus rituximab in participants with previously untreated cll or sll (sequoia). ClinicalTrials.gov Identifier: NCT03336333. Updated November 9, 2023. Accessed October 1, 2024. https://www.clinicaltrials.gov/study/NCT03336333