Payer, Clinical Considerations for Treating Patients With Zanubrutinib

In the second 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 review findings from several studies evaluating the efficacy of zanubrutinib and discuss cost and access considerations for treating patients with this agent.

The first 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 (BTK) 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: Great, thank you. So let's move on to a discussion of the considerations for treating patients with zanubrutinib. I'd like to ask Dr Kittai to review the main takeaways from the three main studies: ALPINE, ROSEWOOD, and ASPEN.

Dr Kittai: Sounds good. The company BeiGene does not make it easy on us. They like to name the trials after various trees, which makes it a little bit confusing, but bear with me here.

The first one is ALPINE. ALPINE was a phase 3 randomized study of zanubrutinib vs ibrutinib for relapsed-refractory CLL. Patients were required to have at least one prior line of therapy, but they could not have received a prior BTK inhibitor. The primary endpoint, which is controversial, was overall response rate as assessed by the investigator.

The reason why I highlight that is this study was unblinded, where the providers knew what drug each patient was receiving. If you have an overall response rate assessed by investigator, there may be some bias there, where the investigator is more apt to rate a good response for zanubrutinib over ibrutinib.

In this trial, they enrolled 415 patients, and they reported the results after a median follow up of 15.3 months most recently at IHA in 2021. They found a significant difference in overall response rate between the two drugs, where the overall response rate for zanubrutinib was 78.3% vs 62.5% in patients who received ibrutinib.

Another controversial thing was that overall response rate in this trial was defined as complete response plus partial response. The reason why I bring that up is that many patients with CLL will have a partial response with continued lymphocytosis, which is a very important endpoint that some of our patients just live in for a very long time. When they actually included partial response with lymphocytosis into the overall response rate characterization, which is how we like to do it in clinical trials, there was no difference in overall response rate observed here.

Another interesting point about this trial was median progression-free survival (PFS), or I should say PFS at a 12-month landmark, was superior in zanubrutinib with 94.9% vs 84% in the ibrutinib arm. So that's something else to look at as time goes on. The question is whether or not these curves will continue to separate as time moves on because 15.4 months is not long enough to make a final assessment.

Last but not least, as we referred to earlier, there were significant differences in toxicity. For one, in terms of any-grade atrial fibrillation, the rate was 2.5% for the zanubrutinib arm vs 10.1% in the ibrutinib arm. Grade 3 atrial fibrillation was the same for both drugs. Hemorrhage was the same as well as high blood pressure, although, of note, patients typically get worsening hypertension over time with the BTK inhibitors, and this is probably too short of a time to really see much of a difference if there is one.

The summary on ALPINE is, as expected, any-grade atrial fibrillation was less for patients treated with zanubrutinib. It was tolerated more than ibrutinib. There were some interesting findings in terms of significant improvement in efficacy, which I think a lot of people thought was unexpected, and further follow-up is needed.

The last thing that I forgot to mention was that zanubrutinib is associated with higher rates of neutropenia, which seems to be an adverse effect of this specific drug, but similar rates of infection when you compare zanubrutinib vs ibrutinib. For this study, I think that endpoint of overall response rate as determined by complete response plus partial response is a little bit flawed, but interesting that there was a significant difference in overall response rate and progression-free survival with zanubrutinib, and it was less toxic.

ROSEWOOD was a phase 2 randomized study comparing zanubrutinib plus obinutuzumab vs obinutuzumab alone for relapsed-refractory follicular lymphoma after receiving over two prior therapies. Of note, patients must have received prior anti-CD20 monoclonal antibody and an alkylating agent in order to go onto this trial. Crossover was allowed, which is always important, and we like to see that in randomized studies.

The primary endpoint here was overall response rate by Lugano. They enrolled 217 patients. The median number of lines of therapy was three, with 25% receiving more than three prior lines of therapy. About 50% of patients were refractory to rituximab in both arms.

After a median follow up of 12.5 months, the overall response rate in the zanubrutinib plus obinutuzumab arm was 68.3% vs 45.8% with obinutuzumab alone. And the duration of response for patients retained to complete response was higher for zanubrutinib plus Obinutuzumab at 18 months. Patient response was about 70.9% of those treated with zanubrutinib. The median progression-free survival was improved for patients who received anubrutinib plus obinutuzumab at 27.4 months vs 11.2 months with obinutuzumab alone.

This is an interesting study. I think that people would argue that using obinutuzumab after three prior lines of therapy is kind of a straw dog comparison. That being said, it's easy to compare zanubrutinib plus obinutuzumab vs obinutuzumab because you're really assessing what the zanubrutinib is doing here.

I think that the other interesting point here is that ibrutinib did not improve efficacy for follicular lymphoma in previous studies, so it is interesting to see zanubrutinib work here. I would like to see a larger study comparing this combination vs more active therapies like lenolidamide plus retixumab or something else, maybe after one prior line of therapy.

Last but not least is ASPEN. ASPEN was also a randomized open-label study that compared ibrutinib vs zanubrutinib for Waldenström’s macroglobulinemia. The primary endpoint was complete response rate plus very good partial responses. This was a long follow-up at 43 months when presented at ASCO.

Patients who were negative for MYD88 were assigned to a separate cohort. Remember MYD88 is a defining mutation for Waldenström’s. They enrolled 229 patients, and they also stratified based off the CXCR for mutation, which is predictive of resistance to BTK inhibitors.

The median duration of response was 41 months in both arms. So the efficacy was very similar. Median time to response, which is important for Waldenström’s, was much faster at 6.7 months in the zanubrutinib arm vs 16.6 months in the ibrutinib arm.

Some patients with Waldenström’s present with very high IgM, which can cause lots of issues with hyperviscosity. Getting their response is very important. Response rates were actually of a statistically significant difference, with 36% in the zanubrutinib arm vs 22% the ibrutinib arm.

Progression-free survival and overall survival were not reached in either arm, and the toxicities were very similar to what we discussed with the ALPINE study, so I won't go over that again. But just to summarize, there was some rate of neutropenia, infections were similar, and there was improvement in atrial fibrillation observed.

Dr Pezalla: Great, thank you very much. Dr Dunn, zanubrutinib is already indicated for adult patients with Waldenström’s macroglobulinemia, mantle cell lymphoma, and relapsed-refractory marginal zone lymphoma. As more data from ALPINE becomes available, this agent will likely also receive approval in the CLL space. How do you foresee payers will approach the coverage for zanubrutinib?

Dr Dunn: I think the short answer is we'll line extend it and we'll just update our prior authorization forms to include it because it's in the label. I think the impetus for us to look at something more critically is cost differences. There are probably two things going on here, or two things that could go on. One would be contracting. There's not a lot of contracting in oncology. Now we have contracting in prostate cancer with PARPis, for example.

But the second issue would be generic. We have three BTKis here. Let's say ibrutinib goes generic. You can look at the TKIs where a lot of people require imatinib before other TKIs. But let's assume here that ibrutinib goes generic. We're going to ask, is there a clinical difference? Can we step the brands behind the generic?

As we just heard, maybe then there is going to be important data from the ASPEN study. Is there a difference in complete response? It's not overall response, it's not progression-free survival, but is there a clinical difference? Is there a big enough difference in safety where we're not going to look at stepping a drug that is much less expensive first? That's kind of the issue.

But the short answer is, short of a generic or contracting, we’ll probably just line extend it.

Dr Pezalla: Great, thank you. Dr Awan, how do you anticipate clinical practice changing if zanubrutinib is approved for the treatment of CLL?

Dr Awan: I think zanubrutinib is very nicely poised to become the front runner in terms of the preferred BTK inhibitor, at least for the time being. We know it's fairly well-tolerated, and it appears to be better tolerated than ibrutinib. Obviously, we already have approval for acalabrutinib, which also is a fairly well-tolerated agent.

Zanubrutinib has its own unique issues with cytopenias, primarily neutropenia, which requires some management, but I feel that zanubrutinib potentially will be the front runner especially in the CLL space.

It's interesting to note the ALPINE study that we just talked about. When we were looking at the differences between acalabrutinib and improved ibrutinib in the Elevate-RR study at two years, we were looking at roughly a 4% to 5% difference. Everybody was excited that acalabrutinib would beat ibrutinib in progression-free survival. But at the end, after a few years, both the curves overlap. So there really isn't any improvement in progression-free survival, and the differences are mostly with regards to toxicity.

Interestingly, for zanubrutinib, the follow-up is relatively short for the ALPINE study, but it does appear that the difference, at least at the early time point as Dr Kittai mentioned, is roughly 10%. Will the curves get caught up later on in the follow-up? We don't know.

But I think the point here, again, is most of the problems that happen with ibrutinib that result in discontinuations happen early on in the treatment course. Once patients go through the first 6 to 12 months, they tend to do well.

Will that be the factor that results in zanubrutinib being the better agent in the long run, or whether this will be a sheer efficacy on target effect? I don't think we'll be able to answer that question for sure. Hopefully the longer follow-up will be able to piece it apart.

But this is exactly where the toxicity, quality of life, and cost related to managing toxicity are the kinds of things that we need to focus on. If you have a drug that is better tolerated and results in lesser admissions, discontinuation, interruptions, lab testing, more follow-up, more frequent follow-up with the primary providers, then I think it's a win-win situation. We'll always go with the drug that is better tolerated if the efficacy is similar, which in zanubrutinib’s case, appears to be better, as least as compared to ibrutinib.

I feel that zanubrutinib has the chance to be the preferred drug for CLL, as well as other low-grade lymphoid malignancies, once it starts getting approval in those indications.

Dr Kittai: I've got a question for Dr Dunn in relation to what for Farrukh just talked about. Can I ask him that question?

Dr Pezalla: Please, go right ahead.

Dr Kittai: Recently, the NCCN guidelines were updated based on the preliminary results from these trials, along with some updated post-marketing analysis for cardiac events on ibrutinib. The NCCN guidelines changed to say that zanubrutinib is now a preferred agent in the front and second lines for CLL, and ibrutinib was downgraded to just recommended.

To Dr Awan's point that we really need to look at the toxicities as opposed to the efficacy, maybe with the comparison of two drugs with the same target, is this enough to support pay of zanubrutinib—that it is now a preferred agent, and I assume safer?

Dr Dunn: It's nice when guidelines actually call out drugs and sequence them. I can't really recall many instances where guidelines actually do that. They pretty much say use a BTKi, or with diabetes it’s metformin, then whatever you want. I would argue that the diabetes guideline is not a guideline. That doesn't guide us to do anything.

It could be. If it's higher up and it's an algorithm and they're saying it should be used before ibrutinib, then yes. But we're talking about two of three things here. We're talking about tolerability/safety and efficacy. The third is cost. And if ibrutinib is generic and it's 1/100th of the cost of the brands, then should that be a consideration with our patients?

I was going to save this for my closing comment, but I think we're heading towards an affordability cliff. There are thousands of oncology drugs in the pipeline, and oncology is largely unmanaged. High-level data has come out in the last three or four years showing that if a patient gets a diagnosis of cancer, they have a 40% chance of declaring bankruptcy within five years.

My concern is if we don't work together and focus not just on tolerability, but on efficacy and cost, then no matter what we do, whether there's access to everything, patients won't be able to actually afford to take these things, and then it doesn't matter.

Dr Kittai: How do you think about the cost of developing atrial fibrillation though? How does that get factored in? I totally agree with you that oncologic drugs are too costly.

Dr Dunn: It depends if you’re looking at drug cost specifically or total cost of care. Cost of care is really hard, to prove what's causing that particular situation. If you go into a hospital, what are you going in for? Is it actually the side effect from the oncology drug, or is it 15 other things that could be coded?

I think where we struggle a little on the payer side is if you look at oncology, multiple sclerosis, rheumatoid arthritis, HIV, and hemophilia where 80% to 95% of total cost of care is drug cost, it's pretty hard to start looking at these things. But yes, it should be factored in.

We should look at medical offsets and the reduction of overall direct costs. Those should be part of the equation. But are they ever going to trump the direct cost of the drug? I don't know.

Dr Pezalla: I'd like to ask Dr Awan and Dr Kittai for some closing comments. And Jeff, if you have anything else, please feel free to chime in at the end.

Dr Kittai: I'll go ahead and start. I think it's a really exciting time in CLL and B-Cell lymphoid malignancies. Our drugs are just getting better in terms of both efficacy and safety. And I think that for our patients specifically, we've had remarkable advances over the last 10 years, and I'm excited to see what's to come.

Dr Awan: I agree. I think these are exciting times. We have so many new, exciting treatments, and we are now arguing about cost and efficacy and toxicity. Ten years ago, we didn't have this luxury. I think it's a great outcome for patients.

We are now a little spoiled because of all we have for managing the disease, that we are now arguing about how we can select one agent over the other based on the different side effect profiles and the cost of care, both to the health system and the patient. I think these are exciting times to be in, and hopefully we can continue to work on these drugs and develop more which are better for our patients, and hopefully our patients can live a normal life.

I think this is exactly the time where you start debating this whole concept of curing cancer. What is a cure, and what does it actually mean? How much should a cure cost? Is a cure even important? These are very important health care discussions, and I think we've been fortunate that we are now in a position to talk about these issues since we are doing such a good job for the vast majority of our patients.

Dr Dunn: Dr Pezalla, I'll just say it's awesome that we have better agents and we're making clinical advancements. It would be nice if we did a better job at de-siloing health care: sharing risk, aligning incentives, all of those buzzwords. I think the shared risk is more between payers and pharma, but aligning incentives, we all want to do the right thing for our patients and for our members.

My fear is if we continue to ignore cost and don't manage this, patients who need these drugs won't be able to take them.

Dr Pezalla: I want to thank all of you for a really terrific discussion. So many important points, and so much exciting work going on in CLL. Thanks to all of you, and thanks to all our viewers for watching today.

This transcript has been edited for clarity.