Lindsey Roeker, MD:
Our discussion today will focus on optimizing the care of patients with CLL through a deeper understanding of BTK inhibitor resistance. We will discuss BTK inhibitor resistance and how this concept guides our clinical practice. To begin, let us review our approach to patients with CLL who require frontline therapy. Dr Davids, when evaluating a patient who requires treatment, what initial tests are you doing?

Matthew S. Davids, MD, MMSc:
We complete a comprehensive genetic profile before starting treatment. This includes FISH testing to identify characteristic cytogenetic abnormalities; regarding key variables influencing treatment, we are looking for del(17p), which is associated with a high-risk form of CLL. We also look at IGHV mutational status, with the unmutated form often underlying somewhat more aggressive disease. We also look for TP53 mutations, which are also associated with a high-risk form of CLL.

It is important to note that these high-risk abnormalities influence the optimal choice of frontline therapy. Our NGS panel includes a range of other genes, which I would say are a little less important right now in terms of their significance in practice. Focusing on the TP53 mutation test is really the key one for patients with CLL.¹

Lindsey Roeker, MD:
We do the exact same thing at Memorial Sloan Kettering Cancer Center. We look at cytogenetics and then IGHV and TP53 mutational status. Our panel also includes BTK as part of the genetic testing, although BTK mutations typically emerge during therapy rather than being present initially. I agree that TP53 testing is the one to focus on when considering treatment options.^1,2

Lindsey Roeker, MD:
Dr Davids, how do you present treatment options to your patients?

Matthew S. Davids, MD, MMSc:
First, I always like to mention clinical trials, because they provide an opportunity to learn more about new treatments and contribute to advancements in treating CLL, despite the availability of many effective therapies now.

As far as the standard treatment options, there are 2 main options in use today. The first is continuous therapy with a covalent BTK inhibitor, of which 3 are now FDA approved for the frontline treatment of CLL: ibrutinib, acalabrutinib, and zanubrutinib. Acalabrutinib can be combined with obinutuzumab, which is another option to consider. The strategy with BTK inhibitors in the frontline setting is to administer them as a continuous therapy until disease progression or until an unacceptable toxicity occurs. Most patients tolerate these drugs well and can stay on them for many years with excellent efficacy.¹   

Another treatment option is the time-limited regimen of venetoclax plus obinutuzumab. This regimen is more intensive initially, involving infusions and then careful monitoring for tumor lysis syndrome during the first couple of months of treatment. However, after 1 year of treatment, patients typically achieve remission and often maintain a durable remission for several years without the need for ongoing treatment.  

Looking ahead, we anticipate a new combination regimen with a BTK inhibitor, likely acalabrutinib, with venetoclax. This regimen will be time-limited, all oral, and approximately 14 months long. It will be a nice option to consider for patients who prefer time-limited therapy without the infusion component.³

Lindsey Roeker, MD:
When evaluating BTK inhibitors for frontline therapy, how do you evaluate the various approved options? Are there safety differences among them that influence your decision?

Matthew S. Davids, MD, MMSc:
Ibrutinib has been used for over 10 years for the treatment of CLL now and has revolutionized the treatment landscape. However, it is well known that ibrutinib is associated with significant cardiovascular issues, particularly HTN and even ventricular arrhythmias in some cases.⁸ In contrast, newer, more selective BTK inhibitors such as acalabrutinib and zanubrutinib appear to have a more favorable safety profile than ibrutinib, particularly with respect to cardiovascular side effects.^9,10

Matthew S. Davids, MD, MMSc:
Recent head-to-head phase III studies in the R/R setting have provided comparative data with these newer BTK inhibitors. The ELEVATE-RR study directly compared ibrutinib with acalabrutinib, and the ALPINE study compared zanubrutinib with ibrutinib. Both studies demonstrated significant safety advantages with the newer, more selective BTK inhibitors over ibrutinib, particularly with regard to cardiovascular toxicities. In addition, these studies showed that the newer BTK inhibitors were associated with lower rates of treatment discontinuation and dose reductions. Based on these studies, it is pretty clear that we should be using either acalabrutinib or zanubrutinib for most of our patients. The challenge remains in the lack of direct comparison between acalabrutinib and zanubrutinib.^9,10

Dr Roeker, could you provide insight on how you differentiate between these 2 newer BTK inhibitors?

Lindsey Roeker, MD:
Considering our discussion of efficacy and treatment selection, it is important to address the role of obinutuzumab in combination with acalabrutinib in the frontline setting. Could you elaborate on how you incorporate obinutuzumab in combination with acalabrutinib and the factors that guide this decision? 

Matthew S. Davids, MD, MMSc:
Data from the phase III ELEVATE-TN study show a PFS advantage for the combination of acalabrutinib with obinutuzumab for an initial 6-month period, followed by continuous acalabrutinib, compared with continuous acalabrutinib monotherapy.⁴

Although the study demonstrated absolute improvement in PFS at 6 years, it is important to note that this finding came from a post-hoc analysis. In addition, there was no difference in overall survival between those 2 arms of the study.  

Given these factors, I sometimes recommend the combination regimen to patients who really want to maximize their initial PFS and are willing to accept the additional inconvenience and potential additional toxicity associated with obinutuzumab.

However, when presented with this option alongside the venetoclax plus obinutuzumab regimen, most patients prefer the time-limited venetoclax plus obinutuzumab option. The patients who opt for acalabrutinib-based regimens typically value the simplicity of a single oral agent. 

As a result, I have not had many patients choose the acalabrutinib plus obinutuzumab combination as a continuous treatment. I am aware of ongoing clinical trials investigating acalabrutinib plus obinutuzumab as a time-limited therapy, which I think is really an intriguing possibility, but it is not yet an approved approach.¹³ Thus, although the continuous acalabrutinib plus obinutuzumab combination is promising, I would likely prefer a time-limited regimen if future data support its efficacy.

Lindsey Roeker, MD:
Let us now turn to the issue of BTK inhibitor resistance. When a patient on continuous BTK inhibitor therapy in the frontline setting begins to start showing signs of relapse, how do you approach resistance? What kind of testing do you perform? 

Matthew S. Davids, MD, MMSc:
De novo resistance to a BTK inhibitor, especially in the frontline setting, is highly uncommon. In my experience, having treated many dozens of patients in this setting, I have encountered primary resistance only once or twice. When primary resistance to a BTK inhibitor is observed, it is important to consider other potential causes. Could this be a Richter transformation? Should a PET scan be ordered to investigate further? It is incredibly uncommon to see primary resistance to a BTK inhibitor so it is generally necessary to investigate further.¹⁴

Resistance mutations typically emerge much later in the course of BTK inhibitor therapy rather than present at baseline. Most resistance mutations arise while the patient is receiving the BTK inhibitor.¹⁵ Thus, testing for BTK mutations prior to starting treatment is generally not necessary, as clinically meaningful BTK mutations are unlikely to be present. 

The question that comes up is when to test for resistance in a patient who is doing well on a BTK inhibitor but starts to show early signs of progression. In most cases, patients will do well with a BTK inhibitor for several years, and then there will be a gradual rise in lymphocyte counts, or maybe some lymph node enlargement, even if the counts remain relatively stable.² In this scenario, I do like to test for a BTK mutation. Although I may not change therapy immediately, it helps provide an early warning if I need to start thinking about alternative options. 

It is also important to note that different covalent BTK inhibitors exhibit varying activity against various mutations. For example, patients who develop the BTK C481S mutation may continue to respond to ibrutinib for a period of time—the median duration in some studies is around 9 months from mutation detection until clinical progression.¹⁶ Dr Roeker, have you observed similar patterns in your practice as well? 

Lindsey Roeker, MD:
Yes, absolutely. The conventional teaching is that progressing on one covalent BTK inhibitors implies cross-resistance across the entire class, which is a fair assumption. If a patient progresses on one covalent BTK inhibitor, it is unrealistic that they will achieve a durable response with a different covalent BTK inhibitor. However, like you mentioned, these drugs have varying binding affinities to different mutations.¹⁷

Let’s return to a question from earlier in the activity.

Lindsey Roeker, MD:
Dr Davids, referring to your earlier example, where a patient who has been on treatment for a while and is now showing rising lymphocyte count or slight nodal enlargement, what are the actual tests you are sending? Could you elaborate on the mechanics of resistance testing?

Matthew S. Davids, MD, MMSc:
In my practice, we use an in-house NGS-based panel that analyzes about 95 genes, including BTK and PLCγ2. PLCγ2 resistance-related mutations can also occur in this context.¹⁵ There are commercially available panels that can be sent if in-house testing is not accessible to you in your practice. It is important to understand the specific mutations and underlying reason contributing to resistance to help guide subsequent therapy decisions. 

That being said, the presence or absence of a mutation does not always influence my choice of subsequent therapy. What is your approach to this, Dr Roeker? 

Lindsey Roeker, MD:
I completely agree with you. We are continuously expanding our understanding of what mutations arise in different contexts. The mutation that we have known about for the longest is the Cys-481 mutation in BTK. Cys-481 is the covalent binding attachment site to BTK for the covalent BTK inhibitors, including ibrutinib, acalabrutinib, and zanubrutinib.^2,15 When explaining this to patients, I use a lock and key analogy. I tell them that in order for this key to work on BTK, the lock needs to have a certain confirmation. If the confirmation of the lock changes, all of a sudden the key does not work. BTK C481 is the mutation that we understand well, largely because it just makes sense. We are discovering more about how other mutations can develop. A lot of this research has been inspired by findings of additional mutations with noncovalent BTK inhibitors. As we are looking backward towards what is happening with covalent BTK inhibitors, we are now learning that mutations can develop not just at the site of covalent binding, but also in other parts of BTK.^14,15 

Matthew S. Davids, MD, MMSc:
Absolutely. Since you mentioned noncovalent BTK inhibitors, let’s transition to discussing second-line and subsequent therapy. If a patient receiving a covalent BTK inhibitor progresses and mutation testing identifies one of the discussed mutations, what treatment options are available to overcome resistance to first-line BTK inhibitors? How do you approach selecting and using these options? 

Lindsey Roeker, MD:
Following initial treatment with a frontline BTK inhibitor, the FDA-approved regimen for subsequent therapy is a venetoclax-based approach. The MURANO study evaluated the combination of venetoclax and rituximab in the R/R setting as a 2-year fixed-duration therapy. This study included a limited number of patients who had previously received covalent BTK inhibitor. This particular patient population had been an understudied group prior to this study.¹⁸

However, we do know that there is significant activity of venetoclax in patients who have progressed on covalent BTK inhibitors, based on clinical practice and retrospective data. In the R/R setting, we could argue that perhaps obinutuzumab may be more effective to pair with venetoclax. Despite prior use of covalent BTK inhibitors, venetoclax-based regimens remain effective.^19,20

In addition, pirtobrutinib, a noncovalent BTK inhibitor, is a newer FDA-approved option for patients who have received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. This approval specifically targets the double-exposed patient population.

Dr Davids, does this align with your approach, and do you have any additional insights? 

Matthew S. Davids, MD, MMSc:
Yes, that is typically how I approach it as well. As you highlighted, we lack robust prospective trial data to guide the choice of venetoclax-based regimen in the postcovalent BTK inhibitor space. There are some data with continuous venetoclax therapy in this setting, but that was from an older trial of patients with a median of 4 prior lines of therapy, most of which were chemoimmunotherapy, making it less applicable to second-line, postcovalent BTK inhibitor scenarios.²¹ 

In the absence of compelling data, I often formulate what I believe is the most effective regimen by extrapolating from available studies. Typically, it involves a combination of venetoclax with obinutuzumab, extending venetoclax therapy to 2 years in the relapsed setting based on the MURANO study, although the added benefit of the second year remains uncertain.

The potential use of pirtobrutinib in the second-line setting is intriguing. It has now been included in the NCCN guidelines but its full approval for second-line use is still pending, meaning use in this setting would currently be off-label.¹ I have encountered several patients who prefer the convenience of a continuous BTK inhibitor in the frontline setting and want to stay in this class for second-line therapy, avoiding more complicated regimens with venetoclax and antibodies. Pirtobrutinib is an option to consider in that setting. 

We are increasingly seeing pirtobrutinib used in second-line, third-line, and later-line settings. Of interest, we are also observing the emergence of different BTK resistance mutation patterns arising with pirtobrutinib.²²

Matthew S. Davids, MD, MMSc:
Dr Roeker, could you elaborate on how resistance develops with noncovalent BTK inhibitors?

Lindsey Roeker, MD:
The discoveries in this space have been very interesting. During the phase I/II BRUIN study of pirtobrutinib, which led to the FDA approval of this drug, we observed the emergence of a new pattern of BTK mutations in patients who progressed on pirtobrutinib.²³

There are a few key mutations that we consider. One type is the gatekeeper mutation, which blocks the drug from accessing the binding pocket. Rather than altering the conformation of the BTK lock so that the key cannot get in, the mutation acts like a cap over the lock, preventing the key from getting near the lock to attempt to make it work.²⁴ 

Another type of mutation we have observed is the kinase-dead mutation. BTK, being a kinase, plays a critical role in cellular signaling by catalyzing chemical reactions. Specific mutations result in loss of kinase activity, rendering BTK nonfunctional. Despite this, downstream signaling continues to occur, suggesting that other parts of the signaling pathway remain active.²² This phenomenon highlights that BTK not only has kinase activity, but also acts as a scaffold for protein assembly and signaling. Both of these types of mutations have been seen in patients who have received pirtobrutinib. Ongoing research indicates that similar mutations might also be occur in patients on covalent BTK inhibitors.

Matthew S. Davids, MD, MMSc:
This is a very interesting recent finding. A publication on the resistance mutation profile of patients from the ELEVATE-RR study, which compared ibrutinib with acalabrutinib in patients with R/R CLL, highlighted some unexpected findings.²⁵ Although BTK C481S mutations were the most common resistance mutations in both groups, a significant proportion of patients progressing on acalabrutinib developed the gatekeeper T474I mutation. This finding was surprising and somewhat concerning, as this T474I mutation appears to confer resistance to pirtobrutinib. However, it is still reassuring that most patients in the BRUIN study who had previously progressed on acalabrutinib responded to pirtobrutinib.

Another mutation that has been observed is the L528W mutation, which is classified as a kinase-dead or kinase-impaired mutation. It has been reported in patients receiving zanubrutinib, raising some concern whether these patients would respond to pirtobrutinib.²⁶ These findings highlight how much there is to learn on this topic.

Matthew S. Davids, MD, MMSc:
One promising development in the field is the emergence of a new class of BTK inhibitor called BTK degraders. As we explore strategies for managing patients who progress on noncovalent BTK inhibitors, this new drug class comes to mind.²⁷

Lindsey Roeker, MD:
BTK degraders are a new class of drugs currently in clinical development. These agents work by getting rid of the BTK protein, rather than just inhibiting it or changing its conformation. Early data on efficacy and safety suggest that these drugs are highly effective and also well-tolerated, even in patients who have previously developed resistance to both covalent and noncovalent BTK inhibitors.²⁸ I believe this is going to be an important class of agents moving forward. 

A key question that arises is how the introduction of BTK degraders will influence sequencing. As we discussed, there are limited data to determine whether a particular sequence, such as A-B-C is significantly better than A-C-B or B-C-A. Understanding how resistance mechanisms develop on a current line of therapy and how these might confer resistance to any future lines of therapy is important. In addition, the role of intermediate intervention is worth exploring. For example, if a resistance mutation develops while a patient is receiving a covalent BTK inhibitor and then they are switched over to venetoclax, could this approach potentially eliminate the resistance mutation clone? Unfortunately, we lack sufficient data on this right now. But I think it is an interesting hypothesis and highlights how much we still have to learn in this space. 

Matthew S. Davids, MD, MMSc:
I agree with you. My inclination is that venetoclax may not completely eradicate a BTK mutant clone. While there are data suggesting that venetoclax can decrease the variant allele frequency (VAF) to undetectable levels, unless venetoclax is curative for CLL, it is likely that the clone will eventually come back, and that is a scenario we need to prepare for.²⁹ Thankfully, we have many treatment options right now for our patients.

It is also interesting that even with BTK degraders, we have already recently seen the first report of a resistance mutation, specifically the A428D mutation in BTK.³⁰ This mutation has also been seen with other BTK inhibitors. This suggests that BTK degraders may develop their own pattern of resistance. However, as you mentioned, potentially rotating through different drugs may continue to buy time as we wait for development of additional treatment mechanisms.

As we look toward the future of CLL therapy, there will likely be some patients who eventually exhaust all lines of BTK inhibitor-based therapies and venetoclax. One of the most intriguing developments in the field over the last couple of years has been the development of immune-based therapies in CLL. I doubted I would ever see it, given the immune system’s dysfunction in CLL. However, there have been several different approaches that have been promising over the last few years.

Lindsey Roeker, MD:
The FDA recently approved chimeric antigen receptor (CAR)-T therapy for treatment of CLL. Lisocabtagene maraleucel was approved for patients with R/R CLL/SLL who have received at least 2 prior lines of treatment, including a BTK inhibitor and a BCL-2 inhibitor. Although the overall response rate to CAR T-cell therapy in CLL remains low, we do see that the patients who do respond achieve durable responses. This makes CAR T-cell therapy a valuable treatment strategy, particularly for higher-risk patients. It is going to take some time to determine how best to incorporate this therapeutic strategy into current treatment protocols.³¹

Also, bispecific T-cell engagers have demonstrated great activity in other lymphomas, and have now shown promising potential for treating CLL. Ongoing studies are investigating the use of bispecific T-cell engagers in CLL, both as monotherapies and in combination with other agents.¹⁹ These studies will help determine how we can incorporate these agents into current treatment protocols as well. 

Additional novel inhibitors targeting the B-cell receptor pathway are currently being studied as well. The field of CLL treatment includes many current options that are incredibly effective as well as a lot of promising emerging options. I believe that the future is bright, both for our patients and for treatment advancements in CLL.