Study Shows Zanubrutinib May Outperform Ibrutinib in Treatment of R/R CLL/SLL
Zanubrutinib demonstrated sustained responses in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia or small lymphocytic lymphoma (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/SLLis 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.
