Kerry Rogers, MD, Talks BTK Inhibitor Sequencing, Cost, Access in CLL

The evolving Bruton tyrosine kinase (BTK) inhibitor landscape for chronic lymphocytic leukemia (CLL) is reshaping how clinicians counsel patients, not just on treatment selection but also on the realities of staying on therapy for years and the systemic challenges that determine who can access care, said Kerry Rogers, MD, associate professor at The Ohio State University Comprehensive Cancer Center–The James.

Rogers walked through how she prepares patients for the long haul of BTK inhibitor therapy, weighing the risk of eventual drug resistance against manageable but persistent adverse effects like hypertension and atrial fibrillation (AFib). She then turned to one of the field’s more pressing open questions: how to sequence treatment once a patient progresses on a covalent BTK inhibitor, particularly given the scarce prospective data on venetoclax combinations in that setting.

The conversation broadened to also address financial toxicity, where Rogers notes that even well-insured patients quietly carry the psychological weight of high drug costs, and to equity, where she argues BTK inhibitors’ oral, at-home convenience may actually ease access for rural and underserved patients compared with infusion-based regimens, while clinical trial representation remains an unresolved challenge across CLL research.

This interview has been lightly edited for clarity.

AJMC: How do you counsel patients about the long-term implications of continuous BTK inhibitor therapy?

Rogers: I think when you’re starting someone on a continuous therapy that they plan to take for years, again, the median progression-free survival [PFS] of ibrutinib in a frontline setting is 8.9 years. In the others, it’s going to be so long; we haven’t seen it yet. Hopefully soon, we’ll get to see some of that, although it’s better, I guess, if we never get a median PFS because people are still doing well. I always counsel people on it being a long-term strategy. They have to be mentally prepared to take the drug for many years. I usually say at least 5 years.

I think there are 2 main risks of taking the drug long-term. One is that the expectation is the CLL will be resistant to the drug by the end of that, meaning the CLL will recur while they’re taking it, and then that class of drugs won’t work anymore, and we do talk about that. Then the other is that there are some [adverse] effects that lead the drug to be discontinued for some patients because they can’t live with them. But there are some [adverse] effects that occur over time in that, actually, the incidence kind of increases the longer you’re on it, [and that] can be a problem. There are things like hypertension and AFib.

I let them know that the longer they’re on the drug, the longer [they] have this continued risk of [adverse effects on the heart]. Bleeding: usually you find out how much of that is occurring early. Actually, some of the things like loose stools, joint pains, and headaches with [acalabrutinib] get better the longer you’re on it, so I do counsel them that some of these [adverse] effects actually improve, but that the heart-related effects, the risk of that continues, and things like bleeding risk don’t decrease if they were to need surgery or take a blood thinner.

AJMC: What do you see as the biggest unanswered questions in BTK inhibitor sequencing, especially for patients who experience disease progression?

Rogers: I think the biggest question with covalent BTK inhibitors in general is that if you give them as a continuous monotherapy, how much is enough or when should you stop this? Since we don’t know the answer to that, most of them are given time until disease progression. Then there are a few unanswered questions there, and the main thing you’re asking is, “How do we think about sequencing after the CLL clone is resistant to a covalent BTK inhibitor?” I think one of the major questions that we don’t really have much information on is, can we do a fixed-duration strategy there, and what is the expected outcome with that?

The prospective study of venetoclax after BTK inhibitors was given—venetoclax was given as a continuous monotherapy—and the median PFS is 2 years, around 2 years, 24 point some months. So, you’re seeing a 2-year benefit. But now we’re saying, “Okay, what if we give obinutuzumab there? What if we use the MURANO regimen?” which is rituximab and venetoclax. “What if we extrapolate from first-line data and give obin and venetoclax? Can we stop the venetoclax at 2 years? Should we stop the venetoclax at 2 years? Does using an anti-CD20 with venetoclax after a covalent BTK inhibitor help the situation?”

I think this kind of use of venetoclax in that setting is a big unanswered question. Everybody seems to be doing a 2-year venetoclax/obinutuzumab scheme, but there’s no prospective data on that, and so although people will tell you it's a standard, we really don’t know what that gets our patients. One, just the use of venetoclax after progression of covalent BTK inhibitors in an era where we combine them with anti-CD20s and tend to stop them at 2 years is a big question.

I think the other major question is, as we start to see BTK inhibitors and venetoclax combinations hopefully move past the front line, can you do some of those after progression on a covalent BTK inhibitor? Like, could you do [pirtobrutinib/ven]? Could that be fixed duration? Is that better than just doing pirtobrutinib or just doing venetoclax? We have a couple investigator-initiated trials here that are starting to generate some of those answers, and those are kind of proof-of-concept phase 2 trials.

I think those are really the unanswered questions. Is there some information now on if you can do venetoclax-pirtobrutinib or pirtobrutinib-venetoclax? And the answer is, yes. Really, you could do either of those, and I think that’s a little more clear. But I think the complete lack of prospective data with venetoclax for anything other than continuous venetoclax monotherapy and the fact that these BTK inhibitor/venetoclax combinations should be studied in that setting is really an important unanswered question that the patients ask me a lot.

Medicaid usually covers these as FDA-approved drugs, so people with less financial resources sometimes are actually getting these faster and at less expense than people with commercial insurance or Medicare.

AJMC: How do you think the oncology community should address the financial toxicity associated with long-term BTK inhibition?

Rogers: Cost is a barrier for patients, but it’s not always personal cost. I’m very fortunate to work at a large center, and we have something called the Medication Assistance Office, where they help patients obtain grant funding to make co-pays affordable. They know all the manufacturer programs, so I’ve never yet not been able to offer someone the therapy we wanted based strictly on cost. I know that that’s not the reality in other places. But I will say that even when the patient’s cost-sharing is $10 a month or $0 or their Medicaid is $2000 a year, they think about the cost all the time.

I have a patient who’s like, “Am I sure I’m actually worth over $100,000 a year in drugs?” Or, I had one whose pet destroyed 1 of their pills on accident and was like, “My pet just ruined $600 worth of drugs by destroying 1 pill.” So, although I don’t think about that much, I think that the patients do. Even when it’s not a personal cost, I feel like the cost of these drugs weighs on them anyway.

I think addressing that actually extends way beyond something we can just do as physicians in hematology. I don’t do health care services research, and I’m grateful for those that do, but this is actually a health system–level problem. These drugs just purchased on the open market in other countries cost markedly less, and this isn’t limited to oncology drugs. I think some of those GLP-1 [glucagon-like peptide 1] receptor agonists, like Ozempic [semaglutide; Novo Nordisk], that have really hit the news—and people keep saying those are super-high-cost drugs—cost a fraction of what these oncology drugs cost. This is really a problem that’s going to have to be tackled by government regulation, drug companies, physician behavior, how we investigate drugs, how our health system works to reimburse drugs, and how we negotiate costs of drugs. There’s going to need to be multiple levels of things going on here before the issue of how much these drugs are costing is addressed.

The only other thing I’ll say about the cost, which I want to add, is that there’s no perfect way to assess cost vs benefit to patients. ASCO has a value framework that I saw a lot of information on, probably about the time ibrutinib was approved, and they actually looked at bendamustine/rituximab [BR] vs ibrutinib. BR, of course, is markedly cheaper from a drug perspective. Infusion costs are there, but even with that, this is cheaper than ibrutinib.

And because ibrutinib was so much more effective—[adverse] effects, quality of life, efficacy in terms of how long people stay in remission—even though it costs markedly more, it actually came out ahead in this value framework. It is showing you that even at the way these drugs are priced, they might actually, and it looks like in every way it's been assessed, still be worth it because of how much better they are for the patients. But I do want to say this is a problem that I do not have an easy answer to.

AJMC: What steps are necessary to ensure equitable access to BTK inhibitors, and what impact does frailty have on this process?

Rogers: When you look at equitable access to BTK inhibitor therapy for patients who don’t live near a city or a CLL center, and when you look at cost, I actually think BTK inhibitors come out better there than drugs like venetoclax, which currently require this ramp-up where you have to go to the office, and also the office or clinic you go to has to have infusion center personnel who know what they’re doing to draw the labs and how to handle it, rapid lab turnaround time. You’ve got to get your results back for the tumor lysis monitoring or find a hospital that can do that and is geared and is set up for it.

I actually think people who live farther away from a major medical center have less access to regimens like venetoclax and obinutuzumab, which require infusions and all this infrastructure to deliver, than BTK inhibitors, which are pretty straightforward. You submit a prescription, and the drug gets mailed to their house. This kind of convenience of a continuous pill therapy, actually, improves access to beneficial therapies for patients in less-resourced areas compared with some of our other cell therapies, which are infusional [and] require this venetoclax ramp-up.

Venetoclax is pretty easy once you’re on it; it’s just pills. But to get started on it—and this doesn’t happen as much anymore, but when venetoclax was used a lot, and we still do this sometimes—people from surrounding clinics in rural Ohio will send the patients to us to do the ven ramp-up, and then we send them back when they’re on it. I think actually BTK inhibitors, by their convenience, are improving access in less-resourced areas.

The finances, actually, currently, of them should be okay, too. There are the manufacturer programs. Medicaid usually covers these as FDA-approved drugs, so people with less financial resources sometimes are actually getting these faster and at less expense than people with commercial insurance or Medicare. I think we’re kind of meeting the mark there, too. I don’t know that those are huge problems with BTK inhibitors specifically.

I do think that one of the barriers initially to their use was just if you weren’t seen at an academic center, people wouldn’t think to recommend continuous therapy. I think that has evolved, and now even people in general practice see that this is so good for their patients and so convenient. We’re talking about general practice oncologists who are seeing a variety of things in a less-resourced setting. CLL is probably not the majority of their practice, so it quite rightfully takes longer to adopt new things. I think that’s not an issue either. I actually think BTK inhibitors are making it easier to access a highly recommended CLL therapy.

[Another] thing that I think is an issue is how we conduct clinical trials and making sure that we capture the patient populations who matter. I do think that across all clinical research in oncology, pretty consistently, although not completely universally, minority populations—non-White populations—are underrepresented.

In CLL, if you look at the demographics of who has CLL, about 92% of those people are White, and 60% some percent of them are men. You are looking at the majority of people living with CLL are White people, and I think we have to be really mindful to make sure that non-White individuals can participate in clinical research and that we make efforts to ensure that they do, because we don’t want 100% of our clinical trial participants to be White when we know that there’s a substantial number of patients, so about 8%, who aren't White.

This is not my research area, but there’s a lot of research and historical reasons that White individuals are more inclined to participate in clinical trials, and I think we need to continue efforts—not just in CLL, but universally—to make sure that our clinical trials really reflect who has the disease and that when we have enough patients to do subgroup analysis of non-White Individuals, to see how they do relative to White individuals in these studies, which have consistently been the majority and should continue to be the majority in CLL, given that 92% of people living with the condition are White. We need to make sure that we really are reflective of who has it.

You have to be eligible to be in a clinical trial, and sometimes you have to be pretty healthy. You have to have good organ function and have to have a decent amount of capacity to be active in order to be in a trial. You’ll be excluded if you don’t. We have had efforts in CLL in several large phase 3 studies to get less fit individuals, people with a higher comorbidity score—which is not a perfect way to capture other health conditions, but does help—or impaired renal function, and older adults. I think there is effort there, but we’re probably never going to capture the really unhealthy population, because those people are probably so busy dealing with their other health conditions that they’re not even interested in taking on being in a trial.

I think continuing to do real-world studies where you look at, kind of retrospectively, what happened to people, continuing to have discussions about patients you see in your clinics, can help inform how we treat those patients. We do actually have a study here that’s an investigator-initiated trial of first-line pirtobrutinib in elderly individuals that is also geared toward enrolling people who are less fit and trying to limit amounts of times they have to come to clinic and things.

I think designing trials either specifically for older, less fit, or both populations in CLL, which we have done as a community, and then just for people who you’re never going to capture in a trial population, which sometimes is their interest. They’ve got so much going on with their health, they don’t want to be in a research study, which is completely fair. Continuing to use real-world evidence to look at those outcomes and discuss strategies among CLL experts and community practice docs for how we treat those patients.