Jennifer A. Woyach, MD, Reflects on the Changing BTK Inhibitor Landscape

Bruton tyrosine kinase (BTK) inhibitors for the treatment of chronic lymphocytic leukemia (CLL) have been on the market for 7 years, during which time they have played an important role in extending survival for patients. Ahead, Jennifer A. Woyach, MD, associate professor of hematology at The Ohio State University in Columbus, Ohio, shares insights about the role of the first-generation agent ibrutinib and the BTK class more generally.

Targeted Oncology: Could you reflect on the BTK inhibitor class and its trajectory within the CLL treatment landscape?

Woyach: BTK inhibitors have changed the treatment paradigm in CLL. They are the first targeted therapies to show a big improvement in progression-free survival compared with standard chemotherapy or chemoimmunotherapy. This class has really changed the approach of treating CLL, where the disease is treated more like a chronic disease for many patients, similar to diabetes or hypertension. Patients can take a pill daily or twice a day for, hopefully, many years. Moving forward, we will continue to see BTK inhibitors used this way in many patients, and now that we have many more targeted agents and increased understanding of disease biology, we have the opportunity to create strategic combinations of therapies with the goals of getting patients off therapy. We also continue to work towards eliminating the disease entirely for many patients.

Targeted Oncology: As the treatment spectrum expands and the BTK inhibitor spectrum has evolved, how has ibrutinib’s role changed? What is the significance of having longer-term data regarding overall survival and duration of response?

Woyach: Ibrutinib is the benchmark by which we judge newer BTK inhibitors. Certainly, it will always have the longest follow-up and probably will always have the most robust data in terms of the number of patients treated on single agent studies through which to evaluate long-term side effects. Compared with some of the second-generation BTK inhibitors, there are advantages to ibrutinib in some patients, including the once-daily dosing and limited drug interactions. There is also a lot of familiarity with ibrutinib since clinicians have been using it for quite a few years.

Right now, having this extensive body of long-term data is important because we are still identifying side effects and patterns of response and relapse. Especially with a drug that patients might take for many years, it is important to have robust long-term data to be aware if any side effects arise with long-term treatment.

Targeted Oncology: How would you assess the relevance of recent analyses evaluating ibrutinib in patients with TP53 alterations? When it comes to evaluating the potential of BTK inhibitors in higher-risk subpopulations, what would you like to see emphasized in future research?

Woyach: The pooled analysis from TP53-altered patients [presented at the ASH 2020 Annual Meeting]1 was really helpful, especially in the front-line setting, because it showed that ibrutinib, and potentially this class of BTK inhibitors, can overcome the negative prognostic value of a TP53 abnormality—at least in the short to intermediate term.

There is a lot of data available with novel agents in the treatment of patients with TP53-altered CLL, since this is a relatively large group in the setting of relapsed disease. Many other genetic abnormalities in CLL are seen much less commonly, so it is only in large studies that we can begin to explore trends. Every bit of information we can collect is important, though, so that we can truly personalize care for patients.

Targeted Oncology: When it comes to the toxicity profile with these agents, what are some of the most notable learnings regarding safety that you’ve taken away from the continued investigation into ibrutinib and the BTK class in a more general sense?

Woyach: As a result of having extended follow-up on many patients, the safety profile of ibrutinib is well articulated and established. We know that there are common toxicities that sometimes cause patients to discontinue therapy but are more quality of life-altering rather than specifically dangerous; these include arthralgias, gastrointestinal symptoms, and fatigue. Then we have toxicities that are much less common but more dangerous, such as atrial fibrillation, ventricular arrhythmias, hypertension, and bleeding. The cardiac toxicities appear to not be entirely dependent on BTK because they are more common with ibrutinib than the more selective second-generation inhibitors.

Targeted Oncology: Looking ahead to the future, what are some of the most important questions that have yet to be answered, and how do you see the BTK landscape continuing to develop?

Woyach: The biggest question right now is whether BTK inhibitors are best administered alone or in combination with other agents, such as venetoclax. There are studies that are designed to answer that question, but it’s going to take a long time to get those results because these drugs work so well. However, this is something that is going to be very important to tease out because it has many implications on toxicity—especially chronic toxicity—as well as financial implications since a combination comes with an upfront increase in cost; it may be more economical in the long-term if a long treatment-free interval can be experienced.

1. Allan JN, Shanafelt T, Wiestner A, et al. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukemia (CLL) with 4 years of follow-up in patients with TP53 aberrations (del(17p) or TP53 mutation): a pooled analysis from 4 clinical trials. Blood. 2020;136(suppl 1):23-24. doi:10.1182/blood-2020-134431