Dr Shadman on the Impetus for Assessing Zanubrutinib Plus Venetoclax in Previously Untreated CLL/SLL

“Arm D was a combination arm and there’s a lot of interest and rationale for combining BTK inhibitors with BCL2 inhibitors, given the distinct modes of action and also the non-overlapping toxicity profile… It’s a unique study in that, as an all-oral regimen, it includes a significant number of patients with 17p deletions and TP53 mutations.”

Mazyar Shadman, MD, MPH, a professor in the Clinical Research Division, medical director of Cellular Immunotherapy, and the Innovators Network Endowed Chair at Fred Hutchinson Cancer Center, detailed the rationale for evaluating the combination of zanubrutinib (Brukinsa) and venetoclax (Venclexta) for the treatment of patients with treatment-naive chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) in arm D of the phase 3 SEQUOIA trial (NCT03336333).

The first cohort of SEQUOIA randomly assigned patients to receive zanubrutinib or bendamustine plus rituximab (Rituxan; BR), Shadman began. Of note, the initial result and the long-term follow-up from the study have been published and previously presented, he explained. He also noted that at the 2024 ASH Annual Meeting, there was a presentation of data that revealed that zanubrutinib monotherapy demonstrated superior outcomes to BR, and was shown to be a well tolerated and efficacious treatment. Additionally, arm C of the study demonstrated the long-term follow-up of zanubrutinib in patients with 17p deletions (del17p), which specifically showed that zanubrutinib generated high efficacy with a favorable safety profile, he contextualized.

Therefore, arm D of the study is a combination arm evaluating zanubrutinib plus venetoclax for the treatment of patients with treatment-naive CLL/SLL, which garnered a lot of interest, as the combination of BTK and BCL2 inhibitors with distinct modes of action and without overlapping toxicity profiles, Shadman continued. Several previous studies have investigated various BTK inhibitors combined with BCL2 inhibitors, particularly venetoclax, he explained. He also emphasized that arm D of the SEQUOIA was a unique, especially as the combination is an all-oral regimen that includes 2 groups of patients: 1 including patients with del17p and TP53 mutations and 1 including patients without the respective abnormalities, he concluded.