Dr Coombs on Notable BTK Inhibitor Combination Studies in CLL

Catherine C. Coombs, MD, associate clinical professor, University of California, Irvine (UCI), UCI School of Medicine, discusses the investigation of notable BTK inhibitor combination trials in patients with chronic lymphocytic leukemia.

In 2023, the standard of care frontline treatment approach in patients with CLL were primarily continuous BTK inhibitor therapy or combination therapy with venetoclax (Venclexta) and obinutuzumab (Gazyva), Coombs begins. However, these standards may soon change based on recent clinical trial data, she says.

One notable study is the phase 3 FLAIR trial (ISRCTN01844152) which investigated the combination of ibrutinib (Imbruvica) and rituximab (Rituxan) compared with fludarabine, cyclophosphamide, and rituximab. The trial demonstrated favorable outcomes for patients receiving the combination regimen, particularly in terms of progression-free survival, Coombs details.

Additionally, trials such as the phase 3 ELEVATE-RR (NCT02477696) noninferiority study and ALPINE (NCT03734016) trial have contributed to the shift away from ibrutinib in the United States, Coombs continues. These trials showed that acalabrutinib (Calquence) and zanubrutinib (Brukinsa), respectively, are safer alternatives with similar efficacy compared with ibrutinib.

Ongoing trials, such as the AMPLIFY trial (NCT03836261) investigating the use of acalabrutinib and venetoclax with or without obinutuzumab vs chemoimmunotherapy, are anticipated to provide updated data on the benefit of a triplet vs doublet treatment regimen in previously untreated CLL, Coombs says.

Acalabrutinib and venetoclax may become a standard in some regions if the trial is positive; however, the comparator arm utilized in this study is less relevant to the paradigm in the United States, since chemoimmunotherapy regimens are less commonly administered, Coombs notes. Accordingly, the MAJIC trial (NCT05057494) will directly compare acalabrutinib and venetoclax with standard venetoclax and obinutuzumab, and a similar phase 3 study (NCT06073821) will compare zanubrutinib plus the BCL-2 inhibitor sonrotoclax (BGB-11417) vs this same regimen, Coombs explains.

Overall, there is optimism that future advancements in CLL treatment will lead to improved outcomes for patients, potentially including the use of oral doublet therapies as frontline options. Continued research and clinical trials are essential to refine treatment approaches and optimize patient care in CLL, Coombs concludes.