Dr Shadman on the Investigation of Sonrotoclax Combination Therapy 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 mechanism of action of sonrotoclax (BGB-11417), highlighting the rationale for combining the agent with zanubrutinib (Brukinsa) in the phase 3 CELESTIAL-TNCLL trial (NCT06073821) in patients with treatment-naive chronic lymphocytic leukemia (CLL).

The ongoing, open-label, multiregional trial is studying sonrotoclax plus zanubrutinib vs venetoclax (Venclexta) plus obinutuzumab (Gazyva) in patients with previously untreated CLL. Sonrotoclax is an innovative next-generation BCL-2 inhibitor, Shadman begins. Currently, venetoclax is the only drug in this category that is widely used, either alone or in combination with anti-CD20 antibodies, as the standard treatment for this disease in both the frontline and relapsed settings, according to Shadman. Preclinical studies have demonstrated that sonrotoclax generates higher efficacy compared with venetoclax, he explains. Additionally, sonrotoclax has a shorter half-life than venetoclax, which offers greater flexibility in dosing schedules, particularly during the ramp-up phase, Shadman emphasizes.

Shadman says his experience with combining BTK inhibitors and BCL-2 inhibitors, such as ibrutinib (Brukinsa) and venetoclax, has been extensive. Numerous clinical trials have already established the effectiveness and acceptable safety profile of these combinations, he notes. The aim with sonrotoclax investigations is to leverage the drug’s enhanced potential by combining it with a next-generation BTK inhibitor, such as zanubrutinib, he reports. Zanubrutinib, when compared head-to-head with the BTK inhibitor ibrutinib, has yielded superior efficacy and a better safety profile, Shadman says.

Given the distinct mechanisms of action of sonrotoclax and zanubrutinib, this combination could offer significant therapeutic advantages, he continues. This study is designed to evaluate the combination of sonrotoclax and zanubrutinib against the current standard of care (SOC). By directly comparing these regimens, investigators hope to establish whether the combination of sonrotoclax and zanubrutinib can provide superior outcomes for patients with CLL, potentially setting a new SOC in this field, Shadman concludes.