Zanubrutinib (Brukinsa; BeiGene) continues to show durable efficacy and a favorable safety profile in treating chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), according to long-term data presented at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition. With follow-up exceeding six years, the data solidify zanubrutinib's role, especially in treatment-naïve and relapsed/refractory settings.
Long-Term Efficacy and Safety
Data from phase 1 studies of zanubrutinib monotherapy and in combination with obinutuzumab (Gazyva; Genentech, Roche) reveal sustained responses in CLL/SLL patients. In treatment-naïve patients, over 75% remained in remission six years after starting treatment. Mazyar Shadman, MD, MPH, noted the deepening responses over time and the absence of new safety signals, reinforcing the drug's favorable profile.
"The drug continues to work really well, with continued efficacy, and I would say a highlight of this follow-up is the fact that we are seeing deepening of responses with longer follow up with a BTKi as monotherapy. So that's great. And second is the fact that we are not seeing any new signal in terms of safety concerns," said Shadman.
Cardiovascular Considerations
Like other Bruton tyrosine kinase inhibitors (BTKis), zanubrutinib is associated with cardiovascular risks such as hypertension and atrial fibrillation. Constantine Tam, MD, emphasized the importance of comprehensive cardiovascular screening at baseline and ongoing monitoring to manage these risks effectively.
"There is an increasing appreciation of the target vessel used these drugs. We do know that patients can get cumulative hypertension... I think it really emphasizes the need for primary providers to do a comprehensive cardiovascular screening at baseline to make sure the patient is fit in terms of cardiovascular health," Tam stated.
Zanubrutinib Compared to Chemotherapy
In the SEQUOIA study, zanubrutinib was compared to bendamustine-rituximab (B-R). Shadman pointed out that zanubrutinib's benefit over chemoimmunotherapy was consistent, irrespective of high-risk features like IGHV mutation. Notably, the complete response rate with zanubrutinib monotherapy approached 20%, a figure not commonly seen with BTKi monotherapy.
Ongoing Research and Combinations
Research efforts are exploring zanubrutinib in combination with other agents, such as the BCL2 inhibitor sonrotoclax. Preliminary data show high efficacy and complete response rates with this combination. The CELESTIAL-TNCLL trial, a phase 3 study comparing zanubrutinib plus sonrotoclax versus venetoclax and obinutuzumab, has completed enrollment, with results anticipated in the coming years.
"That combination shows high efficacy with high quality responses. This combination is now tested against the current standard of care, venetoclax end of obinutuizimab in the first-line setting," Shadman explained.
Zanubrutinib as a Standard of Care
The ALPINE study demonstrated zanubrutinib's superiority to ibrutinib in terms of safety and efficacy. The SEQUOIA study further established zanubrutinib as a standard of care in the frontline setting for patients with triple-naive CLL, showing improved progression-free survival compared to bendamustine-rituximab. These findings reinforce zanubrutinib's role as a key treatment option for CLL and SLL.
