Rajat Bannerji, MD, PhD, Chief, Section of Hematologic Malignancies at Rutgers Cancer Institute of New Jersey/RWJBarnabas Health, speaks on the efficacy and safety findings of the CAPTIVATE study examining the fixed-duration regimen of ibutinib and venetoclax combination therapy in CLL.
Findings of the updated CAPTIVATE study examining the fixed duration regimen of ibrutinib and venetoclax in chronic lymphocytic leukemia (CLL), indicates the combination therapy has potential to provide complete remission and maintain progression-free survival (PFS) in patients, although long-term studies are warranted, said Rajat Bannerji, MD, PhD.
Can you describe the CAPTIVATE study methods, including how you measured MRD [minimal residual disease]?
So, the CAPTIVATE study actually has 2 different parts to it. And the first part of the study was actually presented at the American Society of Hematology meeting in December of 2020, which was a virtual meeting due to COVID-19 by Dr William Wierda of MD Anderson.
The part of the study that will be presented at the American Society of Clinical Oncology meeting by Dr Paolo Ghia is the second part, and I'll describe the 2.
So, the first part of the study, already presented, was 3 cycles of a ibrutinib by itself, then followed by 12 cycles of the combination of ibrutinib and venetoclax. At the end of those 15 cycles, MRD was assessed, and based on MRD results, patients were subsequently randomized. And if patients had undetectable MRD, they were randomized to either placebo or ibrutinib. That data has been presented.
What will be presented now is the second part of the study, similar to a point. Again, 3 cycles of oral ibrutinib to start with, and then 12 cycles of the combination of ibrutinib and venetoclax. However, in this part of the study called the fixed-dose cohort, patients complete treatment after those 15 cycles, and they're done. There's no follow-on or maintenance treatment.
MRD was measured by flow cytometry techniques, and it has a sensitivity of about one over 10–4. So, it could detect one CLL cell in the background of 10,000 normal lymphocytes
Can you discuss the study findings presented at ASCO?
The combination met the primary endpoint of the study, which was in the protocol designed as a complete remission rate of at least 56%. It was well over that. It had a favorable safety profile for the combination of the 2 drugs. The results, in terms of MRD and responses, were similar to the results that we have already presented for the first part of this study.
Certainly, both parts of the study do support the idea of dual oral therapy once daily, 2 oral drugs and chemotherapy, pretreatment for CLL. And this second part of the study that's about to be presented supports the additional characteristic of a fixed duration of treatment 15 months and then done.
Why is it important to get a good response in first-line treatment in CLL? Does this show the value of combination therapy in early treatment?
It is important to get a good deep response with first-line treatment, and I will now pivot a little bit to the data that was already presented for the first part of this study. At the end of the 15 cycles of treatment, 3 of ibrutinib alone and then 12 of the combo, from the first part of this study, we saw that there was a undetectable MRD rate of 75% in the blood and a very similar undetectable MRD of 72% in the bone marrow.
Of these patients, the 1-year disease free survival rate, again presented last year in December, was similar with patients who achieved the undetectable MRD level, whether they got placebo or ibrutinib. And so that level was above 95%.
The 2 groups, again in the previously presented data, the placebo arm had a 95% 1-year disease free survival rate and the ibrutinib arm had 100% 1-year disease free survival rate, but the P value was not significantly different. So, they were comparable.
What that shows us is that added therapy did not give additional benefit and that this combination of the 2 drugs, a limited period of time, very high response rates and very deep remissions, as judged by MRD, allowed you to be free of disease for a prolonged period.
Now, what's going to be very interesting for all of these studies is to see what the long-term PFS rates are, and that data is just not mature enough. So, we'll have to follow this over time, but to go back to your original question, I think the feeling is that if you can get a deep response early on with these combination therapies, that most patients will have a very long period of PFS and a very long period of not requiring additional therapies.
There may be some people, and we don't know yet, but there may be some people where no additional therapy is needed at all. And so again, we'll have to see what the long term data is and follow up for these combination studies.
What are next steps, beyond waiting on the data to mature?
Just in the field in general, there are a number of questions that will need to be addressed. One is, can you guide therapy for individual patients based on their MRD status? And so, can you use that as a decision maker?
So, let's say someone gets undetectable MRD at 12 months, can you stop their treatment then? You've kind of hit that target. For someone who doesn't, do you continue treatment till you get to that level of remission? And I think that's an open question, it's not known. So, can you use this as a biomarker to guide treatment on a patient individual basis? So, I think that's an open question.
Another open question is for the patients who do have recurrent disease, what can you retreat with? And for the patients who end up having any kind of resistance to these 2 drugs, which are mostly active oral drugs up front, what are the options for those patients? And so there's a lot of ongoing research in B-cell malignancies, but also in CLL, in various immunotherapy strategies for the patients who were the very small population who might be resistant or intolerant to these very active oral drugs that we just talked about.
Ghia P, Allan JN, Siddiqi T, et al. Fixed-duration (FD) first-line treatment (tx) with ibrutinib (I) plus venetoclax (V) for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): Primary analysis of the FD cohort of the phase 2 captivate study. J Clin Oncol 39, 2021 (suppl 15; abstr 7501). doi:10.1200/JCO.2021.39.15_suppl.7501