Katie Culos, PharmD, discusses CAPTIVATE study results as well as the role of BTK inhibitors combined with BCL2 inhibitors for first-line treatment in CLL.
Daniel Wojenski, PharmD, BCPS, BCOP: Katie, I know there have been some data that have also been talking about BTK [Bruton tyrosine kinase] inhibitors and BCL2 inhibitors for first-line treatment. What are your thoughts on that? There were some things were presented at ASH 2020 [American Society of Hematology Annual Meeting]. I’d love to pick your brain on what you think about those combinations.
Katie Culos, PharmD, BCOP: As I alluded to before, when we see these new targeted agents that have so much efficacious data on their own, the thought is always that maybe 2 are better than 1. Combining ibrutinib or acalabrutinib with venetoclax is something that is under investigation. There are preclinical models, however, that do support a potential synergistic relationship between the 2 agents. Looking mechanistically in CLL [chronic lymphocytic leukemia] for ibrutinib and how it works, 1 of the functions is that it mobilizes CLL cells away from their protected microenvironment. We know as we learn more about the tumor biology and microenvironments, these malignant cells love to hold up in areas that emit all these nutrients to help them be as wicked as they can be.
One great thing about ibrutinib is that it pulls those cells out of those supportive environments, and it has the ability to reduce the level of myeloid cell leukemia 1 protein, MCL protein. We’re going to pair those qualities with venetoclax, which works by targeting BCL2, and this inhibition will tilt the scales to induce apoptosis of the cells. Essentially, if we can combine the 2 agents together, we’ll pull the cells out from their protective environments and we’ll tip the scales even more toward inducing cell apoptosis.
This was first published in 2019 in the New England Journal of Medicine by Dr [Nitin] Jain and colleagues. They conducted a phase 2 trial with 80 high-risk patients, so 92% of these patients had unmutated IGHV, TP53 aberration, or the chromosome 11q deletion. These were older patients treated with ibrutinib, 420 mg daily. They started that for the first 3 cycles, then added venetoclax at its target dose, which eventually they ramped up to 400 mg daily. These patients continued this combination therapy for up to 27 cycles. However, they were first evaluated after 12 cycles of the combination therapy. What we saw there was a response rate of 88%. Whenever venetoclax is in the building, we’re going to be looking at our MRD [minimal residual disease]. We saw undetectable minimal residual disease in 61% of patients.
As you alluded to before, when we combine therapies, toxicity is always going to be something that we need to assess. We did see in this trial around 60% of patients had grade 3 or higher adverse events. Most commonly it’s going to be cytopenias and neutropenia. However, this year at ASH, there were data that piggybacked on that trial, and that evaluated patients in an alternative dosing schedule after those 12 cycles of combination therapy. Patients underwent 12 cycles with the ibrutinib and the venetoclax and then went through their minimal residual disease assessment.
Based on those results, they were then randomized for different continued therapy. Patients who were MRD negative after combination therapy were randomized to either no further therapy or continued on ibrutinib. If you did have detectable MRD, you were randomized to receive ibrutinib monotherapy or venetoclax plus ibrutinib monotherapy. Jumping off what I was talking about before, what do we do with these MRD data? Do we act or use it in a different way? This study took on that question.
They’ve randomized 149 patients in these 4 treatment arms, and they looked at 30 months at their progression-free survival. And they saw no difference really among all 4 arms. The authors concluded that they support the use of doing that fixed-duration regimen of the combination of venetoclax and ibrutinib vs continuation of therapy that is guided by MRD status after those 12 cycles. That’s probably the most mature study that we have looking at these questions. As you said, it’s very exciting to have all these combinations and different things as options for patients. But as of now, it looks like doing that fixed duration of the combo is best based on the data that we do have.