Paolo Ghia, MD, PhD, Professor of Medical Oncology and Director of the Strategic Research Program on CLL, Università Vita-Salute San Raffaele, Milan, Italy, discusses the phase 2 CAPTIVATE study of first-line ibrutinib treatment plus venetoclax in patients with chronic lymphocytic leukemia (CLL), the data of which are being presented at the virtual 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

Transcript

Hello, my name is Paolo Ghia, and I'm Professor of Medical Oncology at Università Vita-Salute San Raffaele in Milano, Italy, where I am a director of the Strategic Research Program on CLL, where all patients with chronic lymphocytic leukemia are managed.

The idea behind the CAPTIVATE study, in particular the fixed-duration portion of the study that I presented at ASCO, comes from the fact that we now know that we can achieve durable and sustained responses in patients with chronic lymphocytic leukemia when they are treated with continuous treatment with novel inhibitors like BTK inhibitors, but also BCL-2 inhibitors.

Of course, this is very satisfactory for the patient, but still, we would like to stop the treatment after a certain period in order to delay the occurrence of resistance and also the occurrence of potential adverse events with a long-term treatment.

This is the rationale why we designed this study of a combination of the two most active drugs in CLL, ibrutinib, the BTK inhibitor, and venetoclax, the BCL-2 inhibitor, with the idea of stopping the treatment after a determined number of months, which is indeed 12 months, giving the possibility of patient of achieving hopefully sustained responses with a limited amount of therapy.

The study presented is the CAPTIVATE fixed duration, which is a portion of the entire CAPTIVATE study that consists of 2 different parts. One has been presented last year and it is the MRD-guided portion of the study, where patients were treated with ibrutinib for 3 months to debug the patients, followed by 12 months of the combination between ibrutinib and venetoclax.

At the end of the treatment, patients were randomized based on the level of undetectable MRD. Those who reached undetectable MRD were randomized to either placebo or continuous treatment with ibrutinib. Those who did not achieve undetected MRD were randomized to continuous ibrutinib or a consolidation with venetoclax plus ibrutinib, with the idea to personalize the treatment based on the quality of the response.

In the fixed-duration portion of the study that I presented at ASCO, the principle is different. We treated the patient with the same combinations of 3 months of ibrutinib monotherapy followed by 12 months of combination of ibrutinib plus venetoclax, and then all patients stopped the treatment.

The interesting point is that patients achieved a high proportion of undetectable MRD, which was in more than three-quarters of the patient in the peripheral blood, and then around the two-thirds of the patient in the bone marrow, but all patients experienced a long durable remission, with 96 percent of patients still free of progression after 2 years.

This is a study that will have, I would say, almost immediate implication in the real world, meaning that, of course, after the approval of the combination, one can plan to treat the patient with a fixed-duration treatment, so planning ahead treatment that will last 12, 15 months based on design of the study, so patient we know that has to go through the treatment, but also has a perspective to stop the treatment with the possibility of having long and sustained responses.

The next step of course will be, first of all, to follow up the patient and see if and how the patient who will eventually relapse might be treated. Maybe we can use again the double combination and see if and how the patients will respond, or maybe we can just use 1 of the 2 drugs and see how the quality of the response can be achieved, and then follow on that. This is definitely the next step of this study, and of course, another possibility will be also adding, on top of the combination between ibrutinib and venetoclax, an anti-CD20 antibody, like, for example, obinutuzumab, to see if we can achieve even deeper responses, and in particular, a higher number of cases achieving undetectable MRD.

I want to add that despite the fact that we combine 2 of the most important drugs in CLL achieving definitely a very high efficacy, the safety profile of the treatment has been proven to be rather good, meaning that there have not been any unexpected adverse events.

In particular, most of the adverse events were Grade 1 or 2, and those who were a Grade 3 or 4 were manageable and expected that could be neutropenia, given the fact that venetoclax was involved, hypertension as expected from the use of ibrutinib.