Tirabrutinib and CAR T-Cell Therapy Represent Potential Paradigm Shifts in R/R PCNSL

Renewed focus that is driving research in the primary central nervous system lymphoma (PCNSL) field has led to developments regarding the role of CAR T-cell therapies and the second-generation BTK inhibitor tirabrutinib (Velexbru), according to Ashley Sumrall, MD, FACP, FASCO.

In an interview with OncLive®, Sumrall discussed how she approaches CAR T-cell therapies in clinical practice for patients with relapsed/refractory PCNSL. She also dove into clinical trial data surrounding tirabrutinib, including findings from the phase 2 PROSPECT study (NCT04947319).¹ Notably, data from PROSPECT supported a February 2026 new drug application accepted for review by the FDA.² She also touched on the ongoing phase 3 IGNITE trial (NCT07104032) evaluating tirabrutinib vs rituximab (Rituxan) plus temozolomide (Temodar) in patients with relapsed/refractory PCNSL.³

Sumrall is the section chief of neuro-oncology at Atrium Health Levine Cancer Institute in Charlotte, North Carolina.

OncLive: What is the current role played by BTK inhibitors and CAR T-cell therapy in the PCNSL treatment paradigm?

Sumrall: Patients who are struggling with PCNSL are desperately in need of new treatments. We have patients who have recurrence of disease, and they're left with very few options. Looking at the next generation of BTK inhibitors is encouraging for us. We had [phase 1/2] data from a Japanese trial [JapicCTI-173646] with tirabrutinib, and now we have some data in the US, which helps us to be encouraged. More than anything, we're seeing this rebirth of interest in [PCNSL]. We're seeing compounds such as BTK inhibitors, and there are immunotherapy options, including CAR T-cell therapy, in this setting. It's exciting to see some of my colleagues publish data on getting CAR T-cell therapy approved in a clinical trial or in the commercial setting, and using this as an option for patients [with PCNSL].

Are there subsets of patients with PCNSL who may benefit more from CAR T-cell therapy? What are the drawbacks to using CAR T-cell therapy?

[The PCNSL field is] learning as we go. We're building the plane as we fly it, as they say. We're learning that some patients seem to respond better than others to these CAR T-cell therapies; we're not yet sure why. We're doing a better job of identifying the biomarkers that are associated with these different subtypes of lymphoma, which will inform our decisions as we move forward. One unique challenge in this patient population is that we are dealing with patients with a cancer affecting the nervous system. As we know, CAR T-cell therapies and some of the other therapies have some unique neurologic adverse effects [AEs]. What we don't want to do is add insult to injury in this setting. We have to be very cautious about monitoring and aggressively managing these neurologic AEs because these patients already have compromised neurologic systems.

What are the logistical challenges and considerations with CAR T-cell therapy in PCNSL? What do multidisciplinary approaches look like with this therapy?

We face unique challenges with some of our newer therapies, such as CAR T-cell therapies. We find that you have to link arms across multiple disciplines and find cooperation. You need access to an infusion center, you need nurses and pharmacists in that system, and you need a hematologist involved who feels comfortable with that therapy. Oftentimes, you have solid tumor or neuro-oncologists involved as well. There's a lot of coordination that must take place.

There can also be barriers to access for these individuals. These patients can become very sick very quickly, and they could wind up in the hospital, which could throw everything off. Having a nurse navigator and a team that works very closely together is critical to doing the best for these patients.

There's great humility in the world of neuro-oncology, just like in general medical oncology and hematology. When you're taking care of patients with such difficult illnesses, it's very important to seek out your experts and colleagues around you. For me personally, if I meet a patient [for whom] I may want to use an autologous stem cell transplant or a CAR T-cell therapy, I will quickly engage a hematologist who has that dedicated skill set. You also have to have a nursing team that is informed, [along with] a facility where you can deliver this care appropriately. Last but not least, it's very helpful to have neurologists involved who are aware of the potential AEs of these therapies that we give, as well as having an understanding of the underlying illness.

Do you utilize bridging therapies prior to CAR T-cell therapy for PCNSL?

I have not yet been in a situation where bridging therapy needed to be offered before CAR T-cell therapy, but I have talked to colleagues who have been in this difficult situation. As drug shortages and processing times continue to affect us with multiple types of therapies that we give, we have to look toward the future and plan for both a good position where you can quickly move to CAR T-cell therapy, or a more rainy day situation where you have to think about offering a bridging therapy and what that may look like for the patient, as well as the potential associated toxicities.

What differentiates tirabrutinib from other covalent BTK inhibitors like ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa)?

For many years, we've been looking at using BTK inhibitors in the setting of PCNSL. We've had mixed results over the years. Many colleagues [of mine] would tell you that they've used ibrutinib, initially off-label and with mixed results. The issue that we worry about [with using BTK inhibitors in PCNSL] is having a compound that can penetrate the blood-brain barrier and be effective and also tolerable. We worry about AEs such as cytopenias, suppression of counts, and gastrointestinal AEs.

One of the reasons that tirabrutinib was interesting to me was that the data for response were very compelling out of the Japanese study, as well as the tolerability. We have found that [tirabrutinib] seems to be tolerable. If you need to dose reduce, you can do so easily with clear instructions and then reassess in the future. I've had one patient, for example, who developed a rash, we dose adjusted, and then we managed that [rash] easily. This has not been the case with some of the other drugs in that [BTK inhibitor] family.

What were the notable data from PROSPECT for tirabrutinib?

In the PROSPECT trial, we included adults with [PCNSL] who had a median age [of 65.5 years], which is typical for the patients who we see in practice. Next, we wanted to see how many patients responded to this therapy and importantly, [we wanted to see] how long [it took for patients to] respond. The [median] time to response was 1 month. That's important because you want to know if you are a responder as quickly as possible, since you either want to get the patient better quickly or move on to your next line of treatment.

One thing that is very encouraging about using tirabrutinib in this setting of recurrent PCNSL is that the overall response rate was 67%. Within that group, the median duration of response reached [9.3] months, which was impressive in this scenario.

With the FDA currently reviewing a new drug application supported by data from PROSPECT, what would approval of tirabrutinib mean for the PCNSL treatment paradigm?

There really are 2 things that excite me about the fact that tirabrutinib is being considered by the FDA. The first is the fact that we're bringing attention to [PCNSL], which is often neglected. We think about lymphomas in general, but we don't often focus much attention on our patients who [only] have nervous system involvement. I love that we are shining a light on these patients with this rare illness who desperately need this attention.

Second, the fact that the FDA is reviewing this application for tirabrutinib makes me feel encouraged that it could come to market quickly as an option [for patients with PCNSL]. There are many patients who develop recurrent disease [who are] in desperate need of alternative, [bringing] a well-tolerated, oral option to market for these patients is going to be a wonderful tool to have.

What could be the clinical implications of the ongoing IGNITE trial evaluating tirabrutinib vs rituximab plus temozolomide in patients with relapsed/refractory PCNSL?

The IGNITE trial is a great opportunity for patients with recurrent PCNSL. Again, this is a rare condition, and oftentimes these patients are excluded from trials for lymphoma. In this situation, we have patients who've had at least one progression of their B-cell lymphoma affecting the nervous system, and they may [receive] tirabrutinib [monotherapy] or rituximab plus temozolomide. If you review the National Comprehensive Cancer Network Guidelines for how people treat recurrent PCNSL, there are many options that you can continue. One thing that I like about the choice of [rituximab and temozolomide] is that there is good data behind it to support it, and it is well tolerated. When looking for a comparator arm for tirabrutinib, there was a lot of discussion about what to use; ultimately, we settled on a good option.

What are the current unmet needs in PCNSL? How can the field move forward to address those needs?

One of the issues that we have for patients with PCNSL is that we don't know enough about why this is happening to them. Years ago, we would only see this condition happen in an immunocompromised state, such as in individuals with HIV. Now, we're seeing more of it, and we don't truly understand why that's happening. Also, we are learning more about the role of biomarkers, and there are some biomarkers associated with a more aggressive subtype [of PCNSL]. I'm looking forward to learning more about [these biomarkers].

One area where we certainly can do a little more work is examining next-generation sequencing of both cerebrospinal fluid and tissue. At the time of recurrence, it's important to go back and try to learn more about those biomarker patterns.

Are there other developing drugs or ongoing trials in PCNSL you are watching closely?

I’m excited to see what the future holds as we have more interest in this area of managing PCNSL. I am excited to see radiation take a backseat to the systemic therapies because radiation is damaging to the nervous system. Moving forward, I'm looking forward to seeing more clinical trials using CAR T-cell therapy. [I am also looking forward to] more options involving oral agents [so we] can continue to make caring for patients easier and to allow them to live their lives better.

One of the therapies that I'm interested in following is axicabtagene ciloleucel [axi-cel; Yescarta]. A phase 1 study [NCT04608487] was completed, [which evaluated axi-cel in PCNSL], and the results were encouraging. My understanding is that they're moving forward with this therapy, and it is 1 of the key players that we will be following to see how well it works when applied to a larger group of individuals with this disease.

References

1. Nayak L, Grommes C, Kallum A, et al. Tirabrutinib for the treatment of relapsed or refractory primary central nervous system lymphoma: Efficacy and safety from the phase II PROSPECT study. J Clin Oncol. 2025;43(suppl 16):2019. doi:10.1200/JCO.2025.43.16_suppl.2019
2. Deciphera Pharmaceuticals announces U.S. Food and Drug Administration acceptance for filing of new drug application for tirabrutinib in patients with relapsed or refractory PCNSL. News Release. Deciphera. February 16, 2026. Accessed May 13, 2026. https://www.deciphera.com/news/deciphera-pharmaceuticals-announces-us-food-and-drug-administration-acceptance-filing-new-drug
3. Study of tirabrutinib vs rituximab/​temozolomide for relapsed/​refractory primary central nervous system lymphoma (PCNSL). ClinicalTrials.gov. Updated February 2, 2026. Accessed May 13, 2026. https://clinicaltrials.gov/study/NCT07104032