Pirtobrutinib Offers Potential Second-Line Treatment in CLL

Although second-line therapy for patients with chronic lymphocytic leukemia (CLL) remains largely dependent on the frontline treatment choice, the potential emergence of the noncovalent BTK inhibitor pirtobrutinib (Jaypirca) into the second-line setting could offer patients an additional treatment option, according to Jennifer A. Woyach, MD.

“For most patients who [first] received a continuous BTK inhibitor, they could either receive venetoclax [Venclexta] plus obinutuzumab [Gazyva] or rituximab [Rituxan] as their next line [of therapy],” Woyach, the coleader of the Leukemia and Hematologic Malignancies Program and a professor in the College of Medicine at The Ohio State University Comprehensive Cancer Center–James in Columbus, said in an interview with OncLive®. “Pirtobrutinib is [also] now an option in the second-line setting, which is a pretty easy transition from a covalent BTK inhibitor.”

Pirtobrutinib is currently indicated by the FDA for the treatment of adult patients with CLL or small lymphocytic lymphoma (SLL) following at least 2 prior therapies, including a BTK inhibitor and a BCL2 inhibitor.1The December 2023 accelerated approval was informed by data from the phase 1/2 BRUIN trial (NCT03740529), which showed that patients who received the agent (n = 108) experienced an overall response rate of 72% (95% CI, 63%-80%).2

The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for CLL/SLL also recommend pirtobrutinib as an option in the second line for the treatment of patients with resistance or intolerance to prior covalent BTK inhibitor–based regimens, opening the door for its use in the second-line setting.3

In the interview, which took place during Blood Cancer Awareness Month in September, Woyach parsed treatment options in second-line CLL, the current standing of pirtobrutinib in the treatment paradigm, and future research directions in the space.

OncLive: How do you approach treatment selection in the second-line setting of CLL?

Woyach: We have a lot of options for the frontline CLL treatment, and second-line therapy generally is determined by what the patient received for their frontline regimen. A patient who has gotten [first-line] chemotherapy has a different set of options than one who was receiving a covalent BTK inhibitor that was given continuously.

One of the big unanswered questions is, how effective is retreatment going to be with a venetoclax-based regimen? We have options for venetoclax/obinutuzumab, venetoclax/acalabrutinib [Calquence], or all 3, in the frontline setting. There are studies that are being done to try to figure out how effective and durable remissions are going to be with those retreatment options.

That’s the biggest question for me right now. But for a patient who has received a venetoclax-based therapy, another fixed-duration therapy in the second-line setting—provided they’ve gotten a good remission the first time—is a good option.

What factors right do you weigh when considering a potential rechallenge in the second-line setting?

The biggest one is [considering] how long of a remission they had with their first treatment. A patient who received a venetoclax-based regimen and had only a 2-year remission after is very different from one who experiences a 5-year remission. We would expect that the next remission is going to be shorter if you do the same thing again. For a patient who had a 2- or 3-year remission duration after a venetoclax-based regimen, I might still use a venetoclax-based regimen but might change the combination partners. Or, if it was available, give a triplet rather than a doublet. That’s also a patient I would think about a clinical trial for.

How are you using pirtobrutinib in practice since its approval and inclusion in the NCCN guidelines?

This is potentially going to change in the future, given the topline data that’s been released in the frontline setting with pirtobrutinib. [In terms of] pirtobrutinib for relapsed/refractory CLL right now, it’s patient dependent.

For a patient who chose a covalent BTK inhibitor in the frontline setting, did very well with it, and didn’t mind taking the continuous treatment, it’s probably the easiest thing to switch those patients to a noncovalent BTK inhibitor at that point. Pirtobrutinib is well tolerated and easy to take, so that’s a natural transition for a patient who did well on a covalent BTK inhibitor.

That being said, if that patient had a desire to try something time-limited and maybe they didn’t have the opportunity the first time to do a venetoclax-based regimen, this is the time to do it. It’s probably not waiting until the third-line setting—it’s probably doing that in the second-line setting. In that case, I would use pirtobrutinib after a venetoclax-based regimen. [However], we don’t have a lot of data to tell us which one of those [approaches] is going to be the better second-line option.

What are some of the factors you consider when determining whether a patient is ready for subsequent therapy?

Again, it depends on the therapy they were receiving prior. In patients who receive a covalent BTK inhibitor, in general we see relapses occur slowly at first. You might see months, maybe even a year, of just increasing lymphocyte count. If a patient only has an increase in lymphocyte count with no other signs of disease and feels well, I will just let that rise until we see some other signs of disease progression, because at some point it does tend to accelerate rather quickly, and you’re trying to avoid that from happening.

For a patient who received a fixed-duration regimen in the frontline setting we generally would recommend the same criteria to start therapy in the second-line setting as we do in the frontline setting: wait until symptom onset. I generally don’t let it go as long as I would prior to the first therapy, because you know that person is going to be needing therapy, and you’re likely not doing much except for accelerating their symptoms [if you wait to intervene].

For a patient who’s getting treated in the third-line or later setting, I generally don’t let any symptoms develop. There we just look for any signs of disease progression and then switch [therapy] when convenient.

If pirtobrutinib eventually does reach the frontline setting, how do you see that shaking up the CLL treatment paradigm?

The biggest question in my mind is, are we eliminating the use of covalent BTK inhibitors by using a noncovalent inhibitor first? We’re not going to know [the answer to] that for a while. We’re going to have to wait until [we see] relapses on those frontline studies before we understand if the mechanism of relapse is different in the frontline setting than it is in a patient who is taking pirtobrutinib for relapsed CLL.

I’m going to assume that you probably won’t use a covalent BTK inhibitor after a noncovalent BTK inhibitor. Then, there are some populations that might greatly benefit from pirtobrutinib in the frontline setting, especially the older, more frail patients who will likely tolerate pirtobrutinib better than a covalent BTK inhibitor. We know that we can use venetoclax as an option after. Once we better understand what the median duration of remission is going to be for pirtobrutinib in the frontline setting, we can strategize. Should a patient who’s in their 80s receive pirtobrutinib first? If the remissions are as long as those from a covalent BTK inhibitor, then it opens up even more options, because then you still have venetoclax to use afterward and we assume that there’s going to be even more therapeutic options in the future.

If covalent BTK inhibitors are off the table, are there novel agent classes that you can turn to?

BTK degraders are certainly something that we’re seeing work after covalent and noncovalent BTK inhibitors. It’s not off the table if you start with a noncovalent BTK inhibitor, and I see that as a very good option. We also have seen more data with bispecific antibodies alone and in combination, and that’s something that also is likely to play a role in the future. For some patients, CAR T-cell therapy [is also an option]. These are not exactly the same patients who I suggested might get the most benefit from pirtobrutinib in the frontline setting, but there may be patients who are candidates for CAR T and could benefit from not [experiencing] the same adverse effect profile as the covalent BTK inhibitors.

What future research directions in CLL are you the most excited about?

[BTK] degraders, bispecific antibodies, and CAR T-cell therapy are coming forward. There are also other new targets that are being evaluated in CLL, and as we learn more about the biology of the disease, hopefully we’re going to have the next ibrutinib [Imbruvica] and the next venetoclax coming soon. We might even get to the point where we’re able to cure patients, rather than what we can do now, in most cases, which is sometimes functionally cure them, where the remissions outlive the natural lifespan. [We may] get to the point where we are eradicating the disease such that it won’t come back.

References

1. FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. Updated December 7, 2023. Accessed September 25, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic
2. Jaypirca. Prescribing information. Eli Lilly and Company; 2023. Accessed September 25, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059s001lbl.pdf
3. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 3.2025. Accessed September 25, 2025. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf