Comparison of Sonrotoclax plus Zanubrutinib vs. Venetoclax plus Obinutuzumab as First-Line Therapy for CLL

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in Western industrialized countries. For reasons that are not yet fully understood, a subgroup of white blood cells (B lymphocytes)—which are part of the immune system—undergoes malignant transformation. CLL often affects older adults. Treatment for the disease is typically not initiated until patients show symptoms such as fatigue, a tendency to develop infections, or anemia caused by the leukemia cells displacing healthy blood cells. Prior to that, CLL can be monitored so that intervention can occur if the condition worsens. The choice of medications depends on the patient’s overall health, other relevant medical conditions, and genetic changes in the CLL cells. Treatment has evolved; instead of the former standard of immunochemotherapy, which has only limited targeted effects on cancer cells, medications are now used that specifically kill the abnormal cells. This has significantly improved the prognosis for patients while reducing side effects. The optimal combinations of the various CLL therapies currently available have not yet been definitively established. Possible drug classes for targeted therapies include Bruton’s tyrosine kinase inhibitors (BTK inhibitors; e.g., ibrutinib, zanubrutinib) or BCL-2 inhibitors (e.g., venetoclax). Current standard immunotherapies primarily consist of so-called anti-CD20 antibodies (e.g., rituximab or obinutuzumab). Sonrotoclax is a novel, oral BCL-2 inhibitor currently in clinical development. It was developed to improve efficacy against BCL-2-dependent cancer cells and to overcome resistance that can occur with existing therapies such as venetoclax.

The goal of the study is to test sonrotoclax in combination with zanubrutinib, an already approved BTK inhibitor, compared to an established standard of care. To this end, patients will be randomly assigned to two study arms. In the experimental arm, patients will receive the combination of Sonrotoclax and zanubrutinib for 15 cycles (1 cycle lasts 28 days), with Sonrotoclax being administered starting in cycle 4. In the control arm of the study, patients will receive a currently approved first-line therapy consisting of venetoclax, a BCL-2 inhibitor, and obinutuzumab, an anti-CD20 antibody. They will receive this treatment for 12 cycles (1 cycle lasts 28 days). Follow-up will continue for up to approximately 9 years.

Women and men aged 18 and older with chronic lymphocytic leukemia who are scheduled to receive drug treatment for the disease are eligible to participate in the study. No prior systemic treatment for CLL is permitted. Patients must be in good physical condition (ECOG 0–2) and have normal kidney and liver function. There must be no involvement of the brain (CNS involvement).