Exploring Fixed-Duration Ibrutinib and Venetoclax in CLL Treatment

Paolo Ghia, MD, PhD, deputy director of the Division of Experimental Oncology in San Raffaele Scientific Institute in Milan, Italy, full professor of medical oncology, a group leader in the B-cell Neoplasia Unit, and the head of the Strategic Research Program on CLL at the Università Vita Salute San Raffaele, discusses the CAPTIVATE trial (NCT02910583) of fixed duration ibrutinib (Imbruvica) with venetoclax (Venclexta) for the treatment of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and what findings from the trial have been particularly noteworthy.

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0:10 | The CAPTIVATE trial is a phase 2 international trial where we investigated the combination of ibrutinib, the BTK inhibitor, and venetoclax, a BCL2 inhibitor, in frontline patients with CLL. And in particular, this combination was given with 3 months of debulking with the ibrutinib only, and then 12 months of the combination between ibrutinib and venetoclax. The study involved only young patients below 70 years of age.

0:43 | There were 2 different cohorts, not arms. They were not randomized to each other. One cohort was [minimal residual disease (MRD)] driven, so at the end of the 15 months of treatment, patients were randomized based on the level of undetectable MRD. But more importantly, we had the so-called fixed-duration cohort, where patients after 15 months of treatment all stopped the treatment regardless of the level of undetected MRD. And that is actually the regimen that has been approved in Europe, and it can be used now as a standard regimen.

1:19 | The study helped us understand the benefits of a combination treatment for patients with chronic lymphocytic leukemia in the frontline setting. This combination has also been explored in a randomized phase 3 study called the GLOW study [NCT03462719], which involved elderly patients around 65 years of age. These patients were either treated with venetoclax or chlorambucil, the standard chemotherapy for this patient group.

1:48 | The combination treatment showed significant benefits. At the 5.5-year follow-up, data presented revealed that about two-thirds of patients had not experienced disease progression and were still responding to treatment. Of particular interest, patients with unmutated immunoglobulin genes, but without P53 abnormalities, showed similar progression-free survival outcomes. This suggests that the combination treatment is highly effective in high-risk patients, particularly younger patients with mutated immunoglobulin genes.

2:30 | From a safety perspective, there was no notable increase in adverse events compared with previous treatments. The exception was diarrhea, which affected more than 50% of patients, but most cases were grade 1 or 2. All other adverse events occurred at frequencies similar to those seen with single-agent therapies, such as ibrutinib or venetoclax.