Dr Shadman on the Evaluation of Zanbrutinib Plus Sonrotoclax in Treatment-Naive CLL

Mazyar Shadman, MD, MPH, Innovators Network Endowed Chair, associate professor, Clinical Research Division, Fred Hutchinson Cancer Center; associate professor, Medical Oncology Division, University of Washington School of Medicine, discusses the rationale for comparing the efficacy of sonrotoclax (BGB-11417) plus zanubrutinib (Brukinsa) with standard-of-care venetoclax (Venclexta) plus obinutuzumab (Gazyva) in the phase 3 CELESTIAL-TNCLL trial (NCT06073821) of treatment-naive patients with chronic lymphocytic leukemia (CLL).

Several clinical trials have demonstrated the efficacy and acceptable safety profile of venetoclax in combination with ibrutinib for patients with CLL, Shadman begins. However, the adverse effects (AEs) associated with this combination necessitate the development of novel regimens with better tolerability, he says. Research efforts have accordingly shifted to using next-generation BTK inhibitors such as zanubrutinib, which has demonstrated superior efficacy and safety vs ibrutinib in head-to-head trials, Shadman reports. Specifically, zanubrutinib showed significantly improved progression-free survival (PFS) and a more tolerable safety profile, including fewer cardiac AEs.

Additionally, the next-generation BCL-2 inhibitor sonrotoclax is believed to be a more selective and pharmacologically potent inhibitor of BCL-2 than venetoclax, according to biochemical assays, Shadman says. Given their distinct modes of action and proven efficacy as single agents, combining zanubrutinib with sonrotoclax could provide a more effective therapeutic alternative to the SOC this patient population, he states.

The combination is currently under investigation in the open-label, multiregional CELESTIAL-TNCLL trial. To be eligible for enrollment, patients must be 18 years or older with a confirmed diagnosis of CLL, have no prior exposure to treatment for their disease, and measurable disease by CT or MRI. Upon enrollment, patients will be randomly assigned 1:1 to receive either 3 cycles of oral zanubrutinib followed by 12 cycles of zanubrutinib plus sonrotoclax, or a standard regimen of 12 cycles of venetoclax plus 6 cycles of obinutuzumab.

The study’s primary end point is PFS, as determined by an independent review committee using iwCLL 2018 criteria. Secondary end points include complete response rate, undetectable minimal residual disease flow rates, overall survival, overall response rate, duration of response, and patient-reported outcomes. Safety and tolerability will also be reported.

Enrollment for the CELESTIAL trial began in December 2023 and is currently ongoing. The study plans to enroll approximately 640 patients across 251 study sites in 19 countries.