The Role of BTK Inhibition in the Management of Patients With CLL

Amy Goodrich:

Welcome to this virtual roundtable titled “The Role of BTK Inhibition in the Management of Patients with CLL.” I'm Amy Goodrich. I'm a nurse practitioner at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland. Joining me today for this discussion are two of my colleagues, Jill Miller and Kristen Battiato. I would like to hand it over to Jill who's going to talk about treatment and some trials and some of the adverse event data in CLL.

Jill Miller:

Thank you, Amy. As Amy said earlier, my name is Jill Miller. I'm a physician assistant at MD Anderson Cancer Center in Houston, Texas, and I'm going to be discussing different treatment options for CLL and some of the pivotal trials that led to their approval. I'm first going to start out sharing the landscape of treatments for CLL and how they have evolved over the last several decades. It's been a really exciting time in the treatment of CLL. Up until really the last decade, all we really had was traditional chemotherapy agents from the 1960s all the way through the 1990s. We were dealing with the traditional alkylating agents, including chlorambucil. Then we had the introduction of purine nucleosides including fludarabine, pentostatin, and cladribine in the 1970s and 1980s. Then we had the addition of purine, nucleosides, and alkylators in combination in the 1990s.

In the 2000s, we had the introduction of the multiple antibodies that gave us the chemo immunotherapy regimens, fludarabine, cyclophosphamide, and rituximab (FCR), as well as bendamustine and rituximab (BR), which were the mainstay of treatment for a long time, as long as I can remember. In 2014 we saw the introduction of the new small molecule inhibitors, which has dramatically changed the landscape and improved the prognosis for patients with CLL. These include the BTK inhibitors, ibrutinib and acalabrutinib as well as zanubrutinib and others that are in the pipeline and soon to be approved. We also have, and I'll have to always look at those, the phosphoinositide 3 kinase (PI3K) inhibitors, which currently includes only idelalisib. There were two others that were either approved or close to being approved that were then withdrawn by the United States Food and Drug Administration (FDA) due to safety concerns. We'll talk briefly about those.

Amy mentioned earlier the BCL2 inhibitor, which is outside of the traditional BCR pathway, but is a very potent treatment for CLL. This is venetoclax and there are others in the pipeline as well. Then we also have the introduction of a third-generation CD 20 monoclonal antibody obinutuzumab, which has shown significant increased potency over its predecessors, rituximab and ofatumumab. Where things are moving in the future, we have additional BTK inhibitors that include zanubrutinib, which was approved in January of this year (2023), pirtobrutinib, which is soon to be approved. I mentioned earlier we had some additional PI3K inhibitors, but those are no longer in the works for CLL. In terms of the relative toxicities among the three BTK inhibitors, Amy and Kristen, how has this impacted your treatment decision making? How are you using this information in your practice?

Kristen Battiato:

I think it's really pivotal. Specifically, the ALPINE study that was released in December of 2022 gave us a good view of that the cardiac toxicity was significantly less than ibrutinib. And when you're dealing with these older patients who have a history of cardiac disease or at risk for cardiac disease, it's a consideration you want to take into account. I feel like a lot of practices now are more moving towards second-generation BTK inhibitors because they have a more favorable adverse effect (AE) profile at this time. However, I feel like the patients who are on ibrutinib and doing fine on ibrutinib, in our practice, we're leaving them alone because if it isn't broken, don't fix it. Because you can have another set of some side effects with the second-generation BTK inhibitor that you're not having with ibrutinib. So that's how we're practicing at this time. What about you, Amy? What do you think?

Amy Goodrich:

It's exactly the same. We're not switching people unless they have issues. And yes, for those folks who are at high risk and have high risk features, and certainly if they've had a history of atrial fibrillation (AFib) or Aflutter, we use second-generation BTK inhibitors, and this data is really exciting and it's relatively short and hopefully this will stay as the follow-up gets longer for zanubrutinib. But at this point, our highest risk folks, we are using zanubrutinib to try to reduce the incidence of AFib and Aflutter.

Jill Miller:

Yeah, thank you both. I think we're all on the same page in terms of how we're using this information and it's truly nice to have options to have multiple items on the menu to choose from and use with our patients. So thank you.

This next slide looks more at the significant research milestones of CLL and talks about some of the specific discoveries that were made that led to these drug approvals and that's what my talk will be focusing on. This next slide is a table of all the treatments that we have, the therapeutic agents that we have for CLL. You see on the right hand side the traditional chemotherapy agents including chlorambucil, fludarabine, cyclophosphamide and bendamustine. Then we had the CD20 antibodies, starting first with rituximab followed by ofatumumab, which is no longer indicated for CLL, and now obinutuzumab, which is in a lot of our newer combination regimens.

Then we have the BTK inhibitors. I mentioned these earlier: ibrutinib, acalabrutinib and zanubrutinib, and you see the years that they were approved. You see in the blue text the soon-to-be approved BTK inhibitors. The next column are the PI3 kinase inhibitors, and as I mentioned earlier, idelalisib is the only one that has retained its approval for CLL. B-cell inhibitor includes venetoclax now and others to follow. And again, in the other column, lenalidomide still remains a treatment option for CLL and we're also looking at the introduction of CAR-T therapy for CLL treatment. This next slide summarizes the recommended treatment regimens by the National Comprehensive Cancer Network (NCCN). This is in their most recent version that was issued in February of 2023. The preferred regimens you'll see include acalabrutinib plus or minus obinutuzumab, venetoclax plus obinutuzumab, and zanubrutinib. And then in their other recommended B-team regimens, this is where you will see ibrutinib, whether with or without a CD20 antibody, with or without venetoclax, plus the more traditional agents.

In this next slide, I'm going to summarize some of the pivotal trials that led to the approval of the BTK inhibitors, and we'll start out with the ibrutinib studies which include the RESONATE-2 study, the iLLUMINATE, Alliance and ECOG E1912. And then we will go into the studies that led to the approvals of acalabrutinib as well as zanubrutinib.

In the RESONATE-2 study, this study compared ibrutinib versus chlorambucil as a traditional approved treatment. You'll notice that most of the studies with these BTK inhibitors compared against chlorambacil as well as some of the more traditional chemo immunotherapy regimens. And you see in this slide the dramatic difference in progression-free survival (PFS) comparing ibrutinib versus chlorambucil. And this data, the original study was from 2014, but this data was from 2021 and actually goes to 84 months of follow-up and we see that there's a median progression-free survival established for ibrutinib. And more importantly or significantly, we also saw in this study that ibrutinib is actually able to overcome the adverse prognosis of the high-risk markers including 11q unmutated IGHV, as well as TP53 or 17p deletion status.

In the graph on the left-hand side, the top two curves, which is the orange and the purple, showed difference between ibrutinib with deletion 11q and then without deletion 11q. And you may think that there's a typo here, but actually the deletion 11q showed a slightly though not statistically significant favorability toward patients with the deletion 11q. And then the bottom two, the light blue and the dark blue curves, are the two chlorambucil arms. You see the difference between having the deletion of 11q versus not having it. And you see in the chlorambucil without deletion 11q, it's a much more favorable curve as compared with the chlorambucil in deletion 11q. On the right-hand side you see similar graphs for IGHV status and once again you see very similar lines between mutated versus unmutated in the ibrutinib arm versus where you see a more separate curve in the chlorambucil arm.

This next slide is actually from a different study. This is the Alliance study, and this study compared ibrutinib versus ibrutinib plus rituximab versus bendamustine and rituximab. And once again, the progression-free survival was significantly better for both ibrutinib arms versus chlorambucil. And there was actually very little difference between ibrutinib versus ibrutinib plus rituximab. And this particular graph, you see the difference between having a TP53 abnormality versus no TP53 abnormality, and once again, there's virtually no difference in the ibrutinib arms whereas in the bendamustine rituximab arm, you do see as expected the significant difference between having a TP53 abnormality versus no TP53 abnormality. The next study we're going to look at is the Elevate TN, which looked at acalabrutinib with obinutuzumab, acalabrutinib as a single agent, and then chlorambucil plus obinutuzumab. In this graph here you can see the significant advantage of both acalabrutinib arms as compared with the chlorambucil arm.

There was a slight favorability toward the acalabrutinib plus obinutuzumab, 93% PFS at two years versus 87% at two years. And finally the Sequoia study is the study that led to the approval of zanubrutinib and this compared zanubrutinib against bendamustine and rituximab. This is a randomized one-to-one study. We were able to see, once again, significant improvement in PFS comparing zanubrutinib with bendamustine and rituximab. This next slide just shows the difference in the overall kinase selectivity among the different BTK inhibitors. And the three approved ones you see in the middle, acalabrutinib, ibrutinib, and zanubrutinib in the bottom row, and you can see how the selectivity becomes more targeted with each subsequent generation of BTK inhibitor.

And this explains the difference in adverse events between the three BTK inhibitors, and I'm going to go into that in just a little bit. The first study we're going to look at is the ELEVATE-RR study and this is a head-to-head study of acalabrutinib versus ibrutinib and this is in a relapse refractory cohort. There are 533 patients who participated in this study and it was able to show two key endpoints. Number one is a non-inferiority, and so when you look at the progression-free survival, it was very similar for acalabrutinib and ibrutinib, but you had a secondary endpoint decreased incidents of many of the toxicities that we can see with ibrutinib. So, this next slide shows those adverse events, but those include atrial fibrillation and other ventricular arrhythmias, bleeding events, hypertension, infections, interstitial lung disease and/or pneumonitis, and then secondary primary malignancies. And you can see the significant difference particularly in grade three or greater toxicities favoring acalabrutinib. Amy and Kristen, do you have anything to offer regarding this information or anything I've presented so far?

Amy Goodrich:

Well, this is definitely what I see in clinical practice and something that we really spend a lot of time talking to patients about as well and thinking about whether they have a history of AFib or what their hypertension status is, how well controlled things are. Are they on anticoagulants? Just trying to pick the least toxic agent for patients.

Kristen Battiato:

Yes, I think this data has been really pivotal. When you're deciding, when you're choosing a BTK inhibitor, especially in the older patient population, as we know they tend to have more cardiac disease. I think a lot of practices are leaning more toward second-generation BTK inhibitors because of this pivotal data.

Jill Miller:

And certainly this is reflected in the NCCN guidelines which do favor acalabrutinib or zanubrutinib over ibrutinib. And to summarize the ELEVATE-RR study, as I mentioned earlier, the non-inferiority was met on progression-free survival. The median follow up was 40.9 months with a median progression-free survival of 38.4 for both groups, and this is a hazard ratio of 1.0, so virtually no difference whatsoever in toxicities.

Next I'm going to talk about the findings of the ALPINE study. This was a phase III randomized study of zanubrutinib versus ibrutinib in patients relapsed or refractory CLL or SLL. The two arms, arm A was the standard dose of zanubrutinib 160 mg twice daily versus ibrutinib 420 mg daily. And when you looked at the different toxicities, once again, zanubrutinib favored that of ibrutinib with zanubrutinib showing a 2.5 incidence of atrial fibrillation versus 10.1% in the ibrutinib arm. And you actually did see a slightly more favorable progression-free survival with zanubrutinib over ibrutinib. The 12-month event free rate for zanubrutinib was about 95% versus 84% for ibrutinib. That concludes an overview of the key studies leading to the approvals of the different BTK inhibitors. Thank you.