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Ibrutinib Plus Venetoclax Yields Deep Responses in Patients With CLL
Paolo Ghia, MD, PhD, Professor of Medical Oncology, Division of Experimental Oncology, Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milano, Italy, discusses 2-year follow-up results from the phase 2 CAPTIVATE study on first-line ibrutinib plus venetoclax for the treatment of patients with chronic lymphocytic leukemia (CLL). These data were presented at the 2021 American Society of Hematology (ASH) Annual Meeting.
Transcript
My name is Paolo Ghia. I'm working in Milano, Italy, at Universita Vita-Salute San Raffaele where I am a professor of medical oncology. I am directing the research program on chronic lymphocytic leukemia.
The aim in the treatment of patients with CLL is indeed to have very effective treatment that we can stop and discontinue a patient after a certain amount of time. It is, of course, to prevent refractoriness to the drugs and prevents long-term side effects, and also for economical reasons.
That's why we came up with this combination of 2 drugs, one BTK inhibitor ibrutinib, one BCL2 inhibitor venetoclax, with the idea that by exploiting their potential synergy, we could indeed have a very effective treatment that we could discontinue.
That was based on the reasoning that ibrutinib is very capable in mobilizing the cells from the tissues into the peripheral blood, and venetoclax on the other side is very potent in inducing the death of the cells especially when they are circulating in the blood.
The CAPTIVATE study is an international phase 2 study directly to patients affected by CLL who never received therapy. These patients when needing therapy were enrolled to be treated with 3 cycles, 3 months of ibrutinib alone, to debulk the patient, and followed by the combination of ibrutinib plus venetoclax for 12 cycles, 12 months.
At the end of the treatment, the patients were analyzed for the level of MRD, minimal residual disease achieved, and then randomized data on these levels. The patients who achieved the undetectable MRD were randomized to either discontinue the therapy, and so placebo arm, or to continue ibrutinib monotherapy.
On the other side, the patient who did not achieve undetectable MRD were randomized to ibrutinib monotherapy or the consolidation with ibrutinib plus venetoclax. The finding of this study that we now have a 2-year follow-up, and we added an extra year of follow-up compared to the primary analysis. We presented the so-called 2-year disease free survival.
The disease free survival is a little bit different from progression-free survival because it includes the besides the lack of progression and the lack of death, also the lack of MRD relapse.
Within this definition, the interesting part when we analyzed the patient who achieved undetectable MRD and randomized to placebo or ibrutinib, there was no significant difference between these 2 arms. In particular, there was no new event in this additional year of follow-up.
When we look at patients who did not achieve undetectable MRD and were randomized to ibrutinib, or ibrutinib plus venetoclax, we analyzed the progression free survival. The three-year progression-free survival was always more than 95 percent in both arms. More than 95 percent of PFF was also seen in the 2 arms of patient with undetectable MRD, indicating that when we tailor the therapy based on the level of MRD, we can really find the best treatment for every patient to achieve the maximum benefit in every category and every subgroup of patients.
All the findings are quite surprising. We expected high efficacy of the combination. We did not know what to expect in terms of follow-up. The data that there were no new events in the second year of follow-up having always more than 95 percent efficacy in all our arms were somehow surprising, indicating the potency of the combination of these 2 drugs.
It's interesting to note that the same efficacy has been also shown in another study that have been presented at ASH, the GLOW study, which was a phase 3 randomized study where elderly patients with CLL in first line have been randomized to the same scheme as before as the CAPTIVATE—3 months, 3 cycles of ibrutinib followed by 12 cycles of ibrutinib plus venetoclax. Then every patient stopped at the end of the treatment and was compared to the standard arm of immunochemotherapy of chlorambucil plus obinutuzumab. Also that study, the combination of ibrutinib plus venetoclax showed a significant advantage in terms of progression free survival. Very likely, this data will help for the approval of the combinations that hopefully will become soon available in many countries.
At the moment, there is no indication of using undetectable MRD as an endpoint in clinical practice, or to modify the treatment in our patient based on the level of MRD.
Either decrease the treatment, stop the treatment, or add another drug based on the level of MRD. I would discourage of using this tool in the clinical practice because we have no evidence on how we can actually be of benefit for our patients.
The next step will be to identify and understand who are the patients who will less benefit from this potent combination. Maybe these patients will need an extra year of the combination. Maybe these patients will need it continuously with BTK inhibitors.
It will be interesting to analyze these patients from a genetic point of view to understand which genetic feature can help to predict less benefit. We have also to say that the number of patients in progressive or relapsing in this study are so few that we probably need longer follow-up to achieve this goal.
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