Second-Generation BTK Inhibitors for CLL: Clinical, Managed Care Perspectives

In the first part of this roundtable, Edmund Pezalla, MD, MPH, chief executive officer, Enlightenment Bioconsult, moderates a conversation with Adam Kittai, MD, hematology specialist and assistant professor of medicine, Ohio State University; Farrukh Awan, MD, professor of internal medicine, UT Southwestern Medical Center; and Jeffrey Dunn, PharmD, MBA, chief clinical officer, Cooperative Benefits Group. They discuss how second generation Bruton's tyrosine kinase (BTK) inhibitors are changing the treatment paradigm in chronic lymphocytic leukemia (CLL) and how payers evaluate study endpoints to determine coverage for new agents.

The second part of this roundtable discussion can be found here.

Read the full transcript:

Dr Edmund Pezalla: Hello, welcome to our broadcast today. I'm Dr Ed Pezalla, CEO and consultant at Enlightenment Bioconsult, LLC. And our topic today is on Bruton's tyrosine kinase inhibitors and new findings. I would like to introduce our experts on today's panel. Dr Kittai, if I could start with you, please.

Dr Adam Kittai: Happy to be here. My name is Adam Kittai. I'm an assistant professor at The Ohio State University, where I specialize in the clinical investigation and research of chronic lymphocytic leukemia, Richter's transformation, and related disorders.

Dr Farrukh Awan: Hi, I'm Farrukh Awan. I'm at UT Southwestern in Dallas, Texas, and I take care of patients with lymphoid malignancies in CLL.

Dr Jeffrey Dunn: My name is Jeff Dunn. I am a pharmacist by training. I am the chief clinical officer for Cooperative Benefits Group, which is a transparent value-based pharmacy benefit manager based in Utah.

Dr Pezalla: Thank you all for being here with us today. I'd like to talk first about the second generation vs first generation BTK inhibitors in CLL. Dr Kittai, what unmet need led to the development of second generation BTK inhibitors?

Dr Kittai: Ibrutinib was the first generation BTK inhibitor and it was really a marvelous drug. It led to improvements in survival vs chemoimmunotherapy for patients with CLL, both with high-risk and non-high-risk disease. Ultimately, as treatment with ibrutinib and long-term follow up continued, some notable toxicities were picked up. Those included hypertension, bleeding and bruising, and atrial fibrillation. These toxicities can have very real effects on our patients with CLL, who are generally older adults or frail.

The purpose of the second generation BTK inhibitors was to try to develop a drug that was at least equal to the efficacy of ibrutinib but was safer. They looked to create a drug that was a cleaner BTK inhibitor, meaning fewer off-target effects than just targeting the BTK, which was the point of the inhibition to start with.

Thus the drugs zanubrutinib and acalabrutinib were both developed. Both of them are second generation BTK inhibitors. Again, the goal was to create drugs that had fewer off targets effects, allowing for a better and safer adverse event profile, specifically in atrial fibrillation, bleeding, and hypertension.

Dr Pezalla: Thank you. Dr Awan, how are these new agents changing the treatment paradigm in CLL?

Dr Awan: I think they have already changed the way we treat our patients. Fortunately, we now have some head to head comparisons of all of these agents. Not all indications and lines of therapies are included in those comparisons, but I think we have a fairly good feeling that they're equally efficacious. These treatments have almost the same progression-free survival response and disease control rates. Some might be slightly better than the others.

But I think the most important point now is that they possibly have lesser toxicities than the earlier agents, and every new agent in the pipeline seems to be better tolerated, as we focus on B-cell targeting and minimize the off-target effects of these drugs.

In my practice, if two drugs work exactly the same, even a 5% or a 3% decrease in toxicity with an agent is a good enough reason to switch. I think that is being reflected in the more recent guideline updates, where people are leaning more towards using these newer agents, which are better tolerated and potentially less toxic than the earlier agents.

Dr Pezalla: Thank you. Dr Dunn, as these agents undergo more research and we determine whether they can be used in combination regimens, what data and outcomes should payers prioritize when deciding on coverage?

Dr Dunn: That's a good question. I'm not sure there's a whole ton of data that we're going to be looking at. I think the honest answer is the label's going to be the basis for what we do. What we focus on is efficacy and cost. I think the third thing would be safety, but that is more of a patient-provider conversation unless we're trying to sequence drugs.

The way I like to explain it is, there's a diabetes model and an oncology model. In diabetes, we're treating an A1c, and the clinical consequences are years down the road. We can start with monotherapy that may be less expensive, and if we don't get to an A1c goal, then we can move on. In oncology, we can't do that because "failure" is progression or death. If one drug is better, there's not much we can do about it.

We fall back on the label and package insert, but I think we need to look at this from a different perspective and do it in collaboration with the providers because the pipelines are very crowded. Oncology is a very expensive category. It's largely unmanaged. If we don't start doing something a little bit differently, I'm afraid patient affordability is going to be an issue.

Dr Pezalla: Dr Awan and Dr Kittai, what are the key endpoints that you consider? Do you think that they differ from what you're seeing in prior authorizations and other interactions with payers?

Dr Kittai: When we think about clinical trial design in CLL and indolent lymphoma categories, I think the ultimate goal is to see an improvement in overall survival. Unfortunately, that takes many years to prove a difference, specifically in CLL in relapsed-refractory setting. For follicular lymphoma and Waldenström’s macroglobulinemia, you might see a difference sooner because patients don't live as long with those diseases as opposed to CLL, but it still takes a really long time.

In various trials that compared zanubrutinib vs ibrutinib and zanubrutinib plus obinutuzumab vs obinutuzumab, you'll notice the primary endpoints are response rates. It is much easier to show a difference in response rate than it is to show a difference either in progression-free survival or overall survival. The hope is that if you see a difference in overall response rate, this would translate into an improvement in progression-free survival and overall survival, but that's not always the case.

I think that whenever we look at these trials, we have to think about the endpoint that they were hoping to achieve, especially if it's a response endpoint, and think about whether response endpoints in this specific disease type are usually linked to progression-free survival and overall survival. What do you think, Farrukh?

Dr Awan: I agree with you. I think that's what we've been doing. Since a lot of these drugs are similar to each other in terms of their efficacy, historically, we haven't focused on the quality of life improvement in patients who are on one therapy vs another. Most of these kinase inhibitors will be continued indefinitely, so the toxicity management-related cost will end up evening out, and I think that can be an important practical consideration. It's hard to incorporate that as an endpoint, but quality of life metrics are extremely important for any chronic therapy, and that hasn't been looked into for approval purposes. At best, quality of life has been looked at as surrogate endpoint.

I think we need to start focusing more attention on quality of life. How long can the person maintain a productive and useful life while taking these agents, when for all practical purposes, there are very minor or subtle differences or in efficacy? Obviously, we want to go with the more efficacious drug, but at the same time, we also would like to have a drug that is the least toxic and best tolerated since patients will continue on these agents perpetually until progression.

Dr Pezalla: Thank you. Dr Dunn, how do payers take into account toxicities and maintaining quality of life for patients, given that many of the other endpoints will be very similar between the drugs?

Dr Dunn: I think stakeholders in the United States don't do a very good job of factoring in quality of life. If we're talking about drugs that are $10,000 to $20,000 per month, that's very difficult. We would assume that if efficacy is better, quality of life is better. I think it'd be weird if efficacy was the same and quality of life was different. I think we used the studies as surrogate for that. It’s really hard for employers or other people who are purchasing insurance to emphasize quality of life. We probably should do a better job.

We focus on data from the randomized controlled trials, but like I said earlier, I think safety is more of a patient-provider conversation. We're not making a lot of pharma decisions around safety. The honest answer is if pricing of drugs is similar, we're not going to do anything. We're going to leave it up to the provider. But if cost is different, then we're going to start looking at things like efficacy. And then we might have a conversation about preferred drugs, but I really think the primary issues are cost and efficacy.

This transcript has been edited for clarity.