Lindsey Roeker, MD, Discusses Rationale for Investigating an Ibrutinib-Containing Triplet in CLL

At the 2021 American Society of Hematology Annual Meeting, CancerNetwork® spoke with Lindsey Roeker, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center in New York, about reasoning behind testing a combination that includes the Bruton tyrosine kinase inhibitors (BTK) ibrutinib (Imbruvica), the PI3K inhibitor umbralisib (Ukoniq), and the anti-CD20 monoclonal antibodiey ublituximab for patients with chronic lymphocytic leukemia (CLL) in a phase 2 trial (NCT04016805). 

Transcript:

There’s been a lot of excitement about novel agent combination therapy approaches. Certainly for a selected patient population, this is a really good idea. Let’s get a deep response, let’s make sure that we’re treating people to an MRD [minimal residual disease]–undetectable state so that we can have a prolonged treatment-free interval. We also know that BTK inhibitors as monotherapy have been incredibly effective. We have long-term data on ibrutinib [Imbruvica] and acalabrutinib [Calquence] demonstrating long-term efficacy and all of the amazing things that have come with the introduction of BTK inhibitors into the treatment paradigm for CLL.

We know with prolonged exposure to BTK inhibitors that a couple of issues pop up. The first is the possibility for toxicity. We know that there’s cumulative toxicity that occurs over time. Then the second issue is the development of resistance mutations with prolonged exposure to the drug. The third piece is that there are some patients that just don’t want to be on continuous therapies. Our question for this study was, can we take a patient population that has been on a BTK monotherapy and has responded but not achieved an undetectable MRD state and add on medications in order to deepen the response? The combination of PI3K [inhibitors], umbralisib [Ukoniq] and ublituximab [TGTX-1101], is appealing because we know there’s good data for umbralisib and ublituximab in CLL. They’re effective agents in this space. It also allows us to spare venetoclax [Ventclexta] in the combination so that we can use it as a subsequent therapy, and it allows for additional sequencing options down the road.

The idea behind this study, was let’s take this group of patients who have been on ibrutinib monotherapy and let’s add on umbralisib and ublituximab, treat them until they achieve a deep response with undetectable MRD, and then have them enter a period of treatment-free observation. In the study design, we knew that if patients achieved 6 months of treatment-free observation and required retreatment per iWCLL [International Workshop on Chronic Lymphocytic Leukemia] criteria, we would then retreat them with the same combination. This was also asking the question, can we utilize a time-limited ibrutinib–containing regimen and can we retreat with the same regimen upon relapse?

Reference

Roeker L, Leslie L, Soumerai J, et al. A phase 2 study evaluating the addition of ublituximab and umbralisib (U2) to ibrutinib in patients with chronic lymphocytic leukemia (CLL): A minimal residual disease (MRD)- driven, time-limited approach. Presented at the 2021 American Society of Hematology Annual Meeting. December 11-14, 2021. Abstract 395. https://bit.ly/3sKm471