Patient Symptoms and Disease Features Guide Pirtobrutinib Use in R/R CLL

Nicole Lamanna, MD

Pirtobrutinib (Jaypirca)—the first noncovalent BTK inhibitor approved for patients with chronic lymphocytic leukemia (CLL)—has reshaped third-line treatment strategies in this disease space and prompted new considerations regarding treatment sequencing and patient selection as the paradigm grows more complex, according to Nicole Lamanna, MD.

In December 2023, the FDA approved pirtobrutinib for the treatment of adult patients with CLL or small lymphocytic lymphoma (SLL) who have received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.1 This decision was backed by data from the phase 1/2 BRUIN trial (NCT03740529), in which pirtobrutinib elicited an overall response rate of 72% (95% CI, 63%-80%) among patients with CLL/SLL (n = 108).

Subsequently, the confirmatory phase 3 BRUIN CLL-321 trial (NCT04666038) showed that pirtobrutinib elicited efficacy benefits vs idelalisib (Zydelig) plus rituximab (Rituxan) or bendamustine plus rituximab.2 The independent review committee–assessed median progression-free survival (PFS) was 14.0 months (95% CI, 11.2-16.6) in the pirtobrutinib arm (n = 119) vs 8.7 months (95% CI, 8.1-10.4) in the control arm (n = 119; HR, 0.54; 95% CI, 0.39-0.75; P = .0002).

“[The role of] pirtobrutinib is shifting a bit,” Lamanna said in an interview with OncLive®. “It depends on where your patient started treatment and what prior therapies they received. [In the future], pirtobrutinib might fit into the third-line setting, like it does currently, or [in earlier lines] as more data emerge and patients receive alternative therapies in the frontline setting.”

In the interview, Lamanna discussed the current role of pirtobrutinib in the third-line relapsed/refractory CLL setting, considerations for sequencing CLL therapies based on patient symptoms, the importance of waiting for clear indications to initiate a treatment switch in asymptomatic patients, factors that affect decision-making between pirtobrutinib and lisocabtagene maraleucel (liso-cel; Breyanzi), and ongoing clinical trials investigating pirtobrutinib in earlier lines of therapy.

Lamanna is an associate clinical professor of medicine in the Hematologic Malignancies Section of the Hematology/Oncology Division at the Columbia University Herbert Irving Comprehensive Cancer Center in New York, New York.

OncLive: What are some of the patient and disease factors that you consider when potentially selecting pirtobrutinib as a treatment for patients with relapsed/refractory CLL?

Lamanna: Pirtobrutinib is one of the newer tools we have to treat CLL. It's a noncovalent BTK inhibitor, which is different than [the other covalent BTK inhibitors] we currently have, [including] ibrutinib [Imbruvica], acalabrutinib [Calquence], and zanubrutinib [Brukinsa]. However, the noncovalent BTK inhibitors are reversible binders to BTK.

Part of [our traditional treatment decision-making depends on the order in which] these drugs were approved. We had covalent BTK inhibitors approved first, and then we had our first BCL-2 inhibitor—venetoclax [Venclexta]—approved. Now, pirtobrutinib is the first noncovalent BTK inhibitor approved, currently [indicated] in the third-line setting for patients who have progressed on a covalent BTK inhibitor and a BCL-2 inhibitor, although there are limited data [supporting the use of pirtobrutinib in] patients who are intolerant to covalent BTK inhibitors; you can use it in the intolerance setting as well. However, the BRUIN study [investigated this agent] mostly in patients who were either refractory or double refractory to both a covalent [BTK inhibitor] and a BCL-2 inhibitor. Currently, I tend to [use pirtobrutinib] in patients who are refractory to a covalent [BTK inhibitor] or a BCL-2 inhibitor—that [accounts for] most of the patients [to whom] you can offer it in that [third-line] setting.

Typically, we're still [making the decision to switch therapies based on] the same reasons [we have always used to choose treatments] in the frontline and relapsed settings. For patients who need therapy because they're developing cytopenias or progressive, bulky adenopathy, we're still looking for proper indications to treat. We're not necessarily jumping from one [agent] to another without having a reason. This comes up even when we think about other drugs.

A common question I get is: What if [a patient is receiving] a covalent BTK inhibitor? Should you switch? Our goal with CLL is always to consider how we sequence these therapies and how to get the most mileage out of therapies, because CLL is a chronic disease, and—maybe with the exception of some older patients who may only need 1 therapy—younger patients might go from one therapy to another. We are always thinking about sequencing.

If a patient is doing well on a therapy, I'm not necessarily switching [them to another therapy] because that is going to use up another class. If they have an intolerance [to their current BTK inhibitor], then you can move around [to other therapies]. But otherwise, [when deciding] whether to use pirtobrutinib or any other relapse treatment, I would normally [look for] the indications we would [use to choose] pirtobrutinib: progressive disease, cytopenias, new lymphadenopathy, and the constitutional symptoms that go along with that.

What may be the logic behind switching a patient to pirtobrutinib or another therapy vs continuing current treatment if the patient is asymptomatic?

Some patients might start to progress but are relatively asymptomatic. When we think about strategy, we are thinking about the long term. If a patient is currently receiving a BTK inhibitor and their white blood cell [WBC] count is starting to rise, they're starting to develop resistance. [In this case], you can send for resistance mutation testing to [see whether the patient has a] BTK C481S mutation or another mutation, [although this information is mostly just] educational right now.

However, not all patients with progressive disease may have an identifiable resistance mutation. We do this [testing] in the academic setting because there are data showing that besides BTK C481S, there happen to be other resistance mutations, and some of them may have overlapping [targets] between the covalent and noncovalent BTK inhibitors. The question is: In the future, as these tests become more mainstream, will they influence how we sequence therapies? [If we learn that a mutation] is a common [target] for both the noncovalent and the covalent BTK inhibitors, we may not go from [one of those agents to the other], and maybe we will then switch to venetoclax-based therapy. We don't have that granularity of data yet, so [we cannot make treatment decisions based on mutational test results].

Some of the similar mutations that both [covalent and noncovalent BTK inhibitors target] are infrequent and rare. In the BRUIN study of pirtobrutinib in the relapsed setting, [patients' mutational status] didn't affect their responses [with pirtobrutinib]. We don't have a lot of data yet on this, but in the future, resistance mutational testing will potentially be relevant and important, and this may influence the sequencing of drugs.

If a patient is receiving a BTK inhibitor and has a WBC count that is progressing, sometimes you can buy extra mileage out of the drug if they don't have cytopenias, and you do not need to switch them [to another therapy] so quickly. Otherwise, if their disease is progressing, eventually you're going to change therapy, and that could be to venetoclax-based therapy or some other therapy. If you start a venetoclax-based combination that is a time-limited approach where patients come off therapy, you could retreat them, depending on the duration of that treatment. For example, [if a patient had good outcomes with] venetoclax that lasted more than 2 years and they tolerated the therapy well, you could rechallenge them. If this is a relapse in the third-line setting, you could go to [a different agent, like] pirtobrutinib. You have more than one option.

If the patient is asymptomatic, I would still wait until you have a real indication for treating them. [You may not need to treat them] just because their WBC count is going up if their hemoglobin and platelet levels are [stable]. You're going to have the discussion [with the patient, telling them] that they’re eventually going to need treatment again. However, that doesn't mean you necessarily have to put them on therapy sooner.

I'm happy that we have all these targeted therapies and that toxicity issues are improved compared with when we used to give chemoimmunotherapy. However, all these agents [are associated with] potential adverse effects [AEs], including infectious issues. None of these therapies are curative, so if [the patient does not] have an indication to treat yet, I would err on the side of being conservative. I won't treat my patients just because they're starting to progress unless we prove that doing so meaningfully affects their survival, although some trials are trying to address [the potential benefits of] early intervention.

What factors influence your treatment decision-making for patients with CLL who are eligible for both pirtobrutinib and liso-cel?

It's been a long time coming for CAR T-cell therapy in CLL. We started research on this more than a decade ago, but because of the toxicity issues [associated with CAR T-cell therapy], and because we started getting other targeted therapies with far less toxicity, CAR T-cell therapy kept getting relegated further down the line. We're happy to finally have an approval [for CAR T-cell therapy] in CLL because there are many patients who, if they start their CLL journey when they are young, will receive more than 1 therapy. We see patients who relapse after a covalent BTK inhibitor, after venetoclax, and after pirtobrutinib, so we need newer therapies for patients with CLL. Having the [FDA] approval [for liso-cel], which happened in March 2024, is a good adjunct to our toolbox.

One of the benefits of CAR T-cell therapy is that it's a time-limited therapy, in a way. [However, it is still associated with] cytokine release syndrome and potential neurologic toxicity. Thankfully, because CAR T-cell therapy has been around for so long in other disease states, our colleagues who administer CAR T-cell therapy have gotten good at mitigating some of these potential AEs, which has improved with a lot of supportive care and better management.

The problem in CLL is that, unfortunately, in studies like the phase 1/2 TRANSCEND CLL 004 study (NCT03331198), which led to the approval of liso-cel, like many relapsed/refractory studies that we do when we investigate new agents for this disease, some of these patients are on their fourth, fifth, or later lines of therapy—a heavily pretreated group and not a good risk group. In the [TRANSCEND CLL 004] study, 20% of the patients achieved a complete response, and among those 20%, [responses were] durable. [However], for [all other patients, this treatment] falls short.

An update to the TRANSCEND CLL 004 study [presented at] the 2024 ASH Annual Meeting investigated using a BTK inhibitor to augment response to CAR T-cell therapy for patients with CLL. That [combination] doubled the response [rate vs liso-cel alone]. We still have a lot of work to improve upon responses to CAR T-cell therapy in CLL. It's important to get a good response in CLL from CAR T-cell therapy because it will [likely] be durable.

Now that both [liso-cel and pirtobrutinib] are approved [by the FDA], we still consider the patient's comorbidities and how old the patient is. If a patient has progressed on a covalent BTK inhibitor and venetoclax-based therapy, you have to consider other therapies. All other therapies—even pirtobrutinib in [the third-line] setting—are probably going to [yield] limited [responses]. Even in the BRUIN study with pirtobrutinib, the median PFS in double-refractory patients was less than 2 years, so you're going to have to consider other agents.

For example, if I have a young patient who has progressed on a covalent BTK inhibitor and venetoclax-based therapy—truly double refractory—I am going to get them evaluated by my colleagues who administer CAR T-cell therapy, but I'm also probably going to strategize to get their disease better under control because CAR T-cell therapy can be important if you can get them into a good response. Oftentimes, I'll [decide to] get the patient evaluated [for CAR T-cell therapy] and then put them on pirtobrutinib. Sometimes I'll even bridge with pirtobrutinib to CAR T-cell therapy for some of my younger, fitter patients. The good news is, we also have clinical trials, so there are lots of other drugs I might be exploring.

However, when you're [just considering] what's approved—[covalent BTK inhibitors, venetoclax], pirtobrutinib, and liso-cel—you have to evaluate the potential [of each therapy]. If I have an older, frailer patient who I feel may not be able to receive CAR T-cell therapy, I'm going to give them pirtobrutinib. However, for my younger patients, I'm [considering their need for] other therapies down the line; I need to think ahead for them because [their current therapy is] not going to last forever.

For the older patients, if they're not receiving CAR T-cell therapy, I'm considering pirtobrutinib, but then I need to think about what I can do for those in whom the response duration may not last as long. Can you go back to older therapies? Can you add an antibody? You need to become artsy with combinations if you can't get them on a clinical trial with newer agents like BTK degraders, bispecific antibodies, or other agents coming down the pike.

When thinking about pirtobrutinib vs CAR T-cell therapy, you have to consider your patient. What are the goals of treatment? Are they eligible for CAR T-cell therapy? If you're thinking about CAR T-cell therapy [in the future], you should try to have the patient evaluated, because you can collect their cells and freeze them if CAR T-cell therapy is a potential option, because the pirtobrutinib may only last so long, depending upon how heavily pretreated they are.

How might the role of pirtobrutinib in CLL continue to evolve going forward?

There have been lots of studies that are starting to move pirtobrutinib into earlier lines of therapy. There are also clinical trials that have been reported with pirtobrutinib plus venetoclax or pirtobrutinib plus venetoclax and obinutuzumab [Gazyva]—doublets or triplets that are time limited. We may see a lot more time-limited approaches with pirtobrutinib, similar to what we're seeing with covalent BTK inhibitor and venetoclax combinations that have moved into the frontline setting. Some of those have already been included in the National Comprehensive Cancer Network [NCCN] Guidelines. Ibrutinib plus venetoclax was approved in Europe[based on data] from the phase 3 GLOW study [NCT03462719]. And now we have the phase 3 AMPLIFY trial [NCT03836261] regimen of acalabrutinib plus venetoclax with or without obinutuzumab, and that's now on the NCCN Guidelines as well, although it is not yet FDA approved. Studies with pirtobrutinib have moved into both the second- and first-line settings.

We will see a lot of clinical trials read out over the next several years positioning pirtobrutinib as a potential time-limited approach. How then are we going to sequence those kinds of therapies? Do we go from a covalent BTK inhibitor to venetoclax to a noncovalent BTK inhibitor, which is how it is now? What if [pirtobrutinib moves into earlier lines] and is time limited? We have more work to do regarding the potential role of sequencing and where to position pirtobrutinib, either in the frontline or second-line settings.

There are newer agents coming about as well. We will see clinical trials combining these agents with [those with] newer targets, such as BTK degraders or bispecific antibodies. Some clinical trials are adding pirtobrutinib into multiple arms and combining it with different agents. Stay tuned.

The field of CLL is getting a little trickier. I am grateful that we have lots of agents we can use for patients with CLL, but we still have to figure out the best sequencing approach or the best combinations, although there's more than one combination we can [use]. The field is moving quickly, but we still have a lot of data gaps that we need to [fill].

References

1. Jaypirca (pirtobrutinib) now approved by U.S. FDA for the treatment of adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma who have received at least two lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. News release. Eli Lilly and Company. December 1, 2023. Accessed May 9, 2025. https://investor.lilly.com/news-releases/news-release-details/jaypircar-pirtobrutinib-now-approved-us-fda-treatment-adult
2. Sharman JP, Munir T, Grosicki S, et al. BRUIN CLL-321: Randomized phase III trial of pirtobrutinib versus idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) in BTK inhibitor pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma. Blood. 2024;144(suppl 1):886-886. doi:10.1182/blood-2024-198147