“CAPTIVATE is a very important study,” stated Jacob Soumerai, MD, Associate Professor at Harvard Medical School and Massachusetts General Hospital Cancer Center. “The take-home point is that this [ibrutinib plus venetoclax] is highly effective therapy and achieves a high rate of undetectable minimal residual disease [MRD] in the blood [75%] and bone marrow [72%].”

Jacob Soumerai, MD

Based on the study protocol, patients with previously untreated chronic lymphocytic leukemia (CLL) received 12 cycles of ibrutinib/venetoclax. Then, patients were stratified according to MRD response and randomized as follows: those with undetectable MRD were randomly assigned to placebo or ibrutinib; those with detectable MRD were randomly assigned to ibrutinib vs ibrutinib/venetoclax, he explained.

Dr. Soumerai continued: “We can learn more from this study about subsequent management of patients. The 1-year disease-free survival rates [in those with undetectable MRD] were 100% with ibrutinib and 95% with placebo, and this was not significantly different. This is a small cohort not powered to demonstrate a difference between these two arms, but it does drive the point home that ibrutinib/venetoclax as first-line therapy is highly effective. Among those patients who stop therapy after 1 year of ibrutinib/venetoclax, disease-free survival is quite good 1 year later.”

“Another take-home point comes from the cohort of patients with detectable MRD after 1 year who were randomly assigned to ibrutinib or ibrutinib/venetoclax. Continuing the ibrutinib/venetoclax combination resulted in a higher rate of undetectable MRD than ibrutinib alone,” Dr. Soumerai said.

Unanswered Questions and Clinical Implications

“An unanswered question is whether modifying the treatment regimen or duration to achieve undetectable MRD will result in improved outcomes. Will continuing ibrutinib/venetoclax for patients with detectable MRD after 1 year improve progression-free survival? Additionally, the authors plan to assess MRD using more sensitive methods, which can detect and quantify MRD levels below 10^-4. Among patients who had undetectable MRD after 1 year of ibrutinib/venetoclax, I am interested to learn how randomization to ibrutinib or placebo affects MRD levels,” commented Dr. Soumerai.

“First-line regimens for CLL include venetoclax/obinutuzumab and acalabrutinib or a Bruton’s kinase inhibitor (eg, acalabrutinib or ibrutinib) alone or with a CD20 antibody. Although the CAPTIVATE data will not affect how I manage patients in the clinic today, they answer important questions regarding the utility of time-limited venetoclax/ibrutinib as well as questions based on management according to MRD status,” Dr. Soumerai stated. 

DISCLOSURE: Dr. Soumerai has served as a consultant or advisor to AbbVie, AstraZeneca, and Verastem and has received research funding from BeiGene, BostonGene, Genentech/Roche, and TG Therapeutics.