Although pirtobrutinib (Jaypirca) is currently only indicated by the FDA for the treatment of patients with chronic lymphocytic leukemia (CLL) following at least 2 prior lines of treatment, the noncovalent could still have a role in the second-line setting of the disease for certain patients, according to Asad Dean, MD.
In December 2023, the FDA granted accelerated approval to 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 BCL2 inhibitor.1 The approval was supported by data from the phase 1/2 BRUIN trial (NCT03740529), which demonstrated that patients who received pirtobrutinib (n = 108) achieved an overall response rate of 72% (95% CI, 63%-80%) and a median duration of response of 12.2 months (95% CI, 9.3-14.7).2
However, the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for CLL/SLL recommend pirtobrutinib as an option in second-line therapy in the event of resistance or intolerance to prior covalent BTK inhibitor–based regimens.3
“The pirtobrutinib [FDA] indication is following prior a covalent BTK inhibitor, as well as prior BCL2 [therapy],” Dean said in an interview with OncLive. “However, the way it is designated in the NCCN guidelines is that following a covalent BTK inhibitor, you have that option [to use pirtobrutinib]. I like that flexibility because we don’t have an indication for combination BTK plus BCL2 inhibition in the frontline setting. [The combination] is recognized by the NCCN, but we do not have an FDA approval. Based on NCCN as a platform and foundation, I find it advantageous to be able to move to a noncovalent, reversible BTK inhibitor like pirtobrutinib following progression on a covalent BTK inhibitor.”
Dean is a physician at Texas Oncology as well as an assistant professor in the Division of Hematology/Oncology at UT Southwestern Medical Center, both in Dallas.
In the interview, which took place during Blood Cancer Awareness Month in September, Dean discussed the treatment landscape of second-line CLL, the role of pirtobrutinib, and other agents of interest in the space.
OncLive: How do you approach treatment selection in the second line for a patient with relapsed/refractory disease? What are some of the unmet needs in that setting?
Dean: We have revolutionized therapy for [patients with] CLL. When I was a fellow 25 years ago, [the standard of care] was fixed-duration chemoimmunotherapy. The advent of BTK inhibition has revolutionized the way we approach treatment.
In my practice, most of my patients in the frontline setting are receiving a covalent BTK inhibitor. There are some patients who are hesitant to be on continuous therapy, and for those patients in the frontline setting, I have used fixed-duration anti-BCL2 therapy along with anti-CD20 therapy. These have both proven to be effective regimens in the frontline setting; however, as is the case in other malignancies, resistance can develop.
In the second-line setting [following] a covalent BTK inhibitor, [in the event of] disease progression, I will then change to a BCL2-directed therapy. With that being said, NCCN guidelines recommend consideration, following a covalent BTK inhibitor, of either a BCL2 inhibitor or a noncovalent, reversible BTK inhibitor.
Is there a role for rechallenge with a covalent BTK inhibitor or BCL2 inhibitor in the second line?
If a patient is intolerant to one covalent BTK inhibitor, then rechallenge can certainly be possible [without] losing efficacy. I would also say that molecular profiling is important. It is very important to know if [a patient] has deletion 17p, deletion 11q, [or] a TP53 mutation. If they have unmutated or mutated immunoglobulin heavy chain status, that could also influence consideration of a rechallenge.
The problem with rechallenge upon [disease] progression is the development of resistance mutations. Those mutations for the BTK inhibitors most commonly happen in the C481 binding region of the BTK enzyme. However, [a patient] can also have BCL2 mutations, so you have to be careful about rechallenge because of the of binding of the particular enzyme. If [BLC2] is mutated, it’s unlikely to respond to a treatment within the same class.
How do you weigh rechallenge vs moving to a new therapy if there is an approved and indicated option?
For me, rechallenge makes most sense if a patient is intolerant because it’s unlikely that you have been able to exhaust the lifespan of a particular treatment. Therefore, the mechanistic approach would continue to work.
What could signal that a patient may be ready to move on to pirtobrutinib?
The beauty of the advent of pirtobrutinib is having noncovalent, reversible binding, which allows you to overcome resistance. If a patient is progressing clinically, they could have worsening blood counts, cytopenias, anemia, thrombocytopenia, or their white [blood cell] count could be escalating. It is important to note that you do get a transient lymphocytosis following initial initiation of a BTK inhibitor due to discombobulation and egress into the peripheral blood, but that subsides in time. If you’re seeing after months or years on a BTK inhibitor and the white [blood cell] count is starting to elevate, that could mean you’re losing response.
If a patient develops progressive or worsening lymphadenopathy, it’s important to biopsy to make sure that they’re not transforming to a higher-grade lymphoma. If they are getting progressive splenomegaly, or they’re having recrudescence of B symptoms [such as] fevers, night sweats, weight loss, or worsening fatigue, those would all be indicators that you are losing response or developing resistance, indicating a need to change therapy.
Where does CAR T-cell therapy fit alongside pirtobrutinib as it’s currently being used?
CAR T-cell therapy is a remarkable way to harness an individual’s immune system to combat their cancer. Within CLL, it’s [used] in heavily pretreated patients. It is important to note that the response rate can range anywhere from [approximately] 40% to 90%, and the complete response [CR] rate is [approximately] 18% to 68%.
Also, studies have shown that if you are able to obtain a CR in the first year, your progression-free survival [rate] is much better at five years. There have also been data to suggest that you can have improved response by combining it with a BTK inhibitor such as ibrutinib [Imbruvica]. The data are forthcoming, and we will need to see in time where CAR T-cell therapy fits.
It is an expensive therapy, although the advantage is that your treatment is done in a fixed timeframe, and, if you can achieve that type of response, then it’s unlikely to develop the resistance that we see with continued usage of BTK and BCL2 inhibitors. You can also develop resistance to pirtobrutinib as well. The promise of CAR T is taking that out of the equation, but it is still far from being moved into an earlier setting.
What other areas of research or novel agents could also help improve treatment options within the second-line setting and beyond in CLL?
I’m particularly excited about research looking at BTK degraders through ubiquitination, [which is] essentially proteasome destruction. That is an exciting class that is presently under investigation.
There have also been promising phase 1 data looking at bispecific therapies, specifically epcoritamab-bysp [Epkinly]. In the [phase 1b/2] EPCORE CLL-1 trial [NCT04623541], which included heavily pretreated and high-risk patients with CLL with a primary end point of ORR. The excitement of bispecific therapy and tempered toxicity related to immune effector cell–associated neurotoxicity syndrome is an issue that we have to contend with. As we become more comfortable with bispecific therapies in other diseases, it will help us when the time comes to fit them into the equation for CLL.
With September being Blood Cancer Awareness Month, what is your main message for colleagues on the current state of the second-line setting of CLL?
It’s an exciting time for patients and for research development taking place in CLL. This is a disease that tends to affect older patients. Ultimately, the goal is to provide safe, effective treatment that doesn’t hinder quality of life or create undue risk that would outweigh benefits, since we’re treating an older population.
That being said, there are also younger patients who may develop [CLL], and intensified, aggressive approaches are necessary in order to ensure greater longevity and improvement in overall survival. I feel optimistic about how the science continues to develop, and as a practicing oncologist in the community, I’m so gratified by how I have seen the approach to CLL change during my career, and having oral targeted agents available is tremendous. It helps patients be able to take control of their lives, empowers them to take charge of their health, and provides a convenient way to have effective treatment that is not only tolerable but safe. The future is incredibly promising, and I look forward to seeing how some of the therapies that I mentioned weigh into our considerations for our patients to improve their lives.
References
- FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. Updated December 7, 2023. Accessed September 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic
- Jayprica. Prescribing information. Lilly; 2023. Accessed September 19, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059s001lbl.pdf
- NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic leukemia, version 3.2025. Accessed September 19, 2025. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf