Tirabrutinib May Shift the R/R PCNSL Treatment Paradigm Toward Improved Tolerability

The second-generation covalent BTK inhibitor tirabrutinib (Velexbru) may be a new treatment option for patients with relapsed/refractory primary central nervous system lymphoma (PCNSL), as it maintains strong responses and penetrates the blood-brain barrier, as well as simultaneously reducing adverse effect (AE) burdens.

Previously reported positive data from the phase 2 PROSPECT study (NCT04947319) with tirabrutinib-based treatment in this patient population have helped build anticipation for results from the ongoing phase 3 IGNITE study (NCT07104032) evaluating the agent as monotherapy vs rituximab (Rituxan) plus temozolomide (Temodar) in patients with relapsed or refractory PCNSL.^1,2

Moreover, data from PROSPECT helped support the February 2026 FDA acceptance of a new drug application(NDA)seeking the approval of tirabrutinib for this indication.³

“There’s a better AE profile [with tirabrutinib] than with ibrutinib [Imbruvica] for sure. There has been no head-to-head comparison, but [toxicities], especially cardiac [toxicities], that we see with ibrutinib [are not typically experienced in] patients who are receiving tirabrutinib,” said Christian Grommes, MD, in an interview with OncLive®.

Grommes is a neuro-oncologist and early drug development specialist at Memorial Sloan Kettering Cancer Center in New York, New York.

“The issue we worry about [with using BTK inhibitors in PCNSL] is having a compound that can penetrate the blood-brain barrier and be effective and tolerable,” Ashley Sumrall, MD, FACP, FASCO, added in another interview with OncLive. “One of the reasons that tirabrutinib was interesting to me was that the data for response, as well as tolerability, were compelling out of the phase 1/2 Japanese study [jRCT2080223590]. 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.”

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

What key data were previously reported with tirabrutinib from PROSPECT?

Data from PROSPECT, which were presented at the 2025 ASCO Annual Meeting, showed that an overall response rate (ORR) of 67% (95% CI, 52%-80%) and a complete response (CR) rate of 44% (95% CI, 29%-59%) were achieved by patients who received tirabrutinib (n = 48).² Notably, patients who received tirabrutinib experienced a median duration of response (DOR) that was 9.3 months (95% CI, 4.6-14.6) and a median progression-free survival (PFS) that was 6.0 months (95% CI, 5.3-11.1).

“When we see that 67% of patients have a response [with tirabrutinib], it is something we have expected with a BTK inhibitor based on data for ibrutinib,” Grommes commented. “The striking finding was that the median DOR was 9.3 months in those who responded. [These are] nice response data. We have seen that BTK inhibitors [induce] high response rates, but the problem is that PFS and DOR [are often] limited. [Therefore, these data] have added to the value of using BTK inhibitors for PCNSL.”

The median DOR data were coupled with strong time to response (TTR) data in the trial, with patients achieving a median TTR of 1.0 month (range, 0.9-3.7).

“That’s important because you want to know [whether a patient is] 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,” Sumrall said.

Regarding safety, any-grade treatment-emergent AEs (TEAEs) that led to dose reductions were experienced by 10% of patients, and serious any-grade TEAEs occurred in 44% of patients; 35% of patients had grade 3 or higher serious any-grade TEAEs. Cardiac AEs were all grades 1 or 2 and experienced by less than 10% of patients.

What are the notable design aspects of IGNITE?

“[IGNITE] is the first phase 3 trial in the recurrent or refractory PCNSL setting. It compares [standard rituximab plus temozolomide] with tirabrutinib monotherapy, which is an interesting guideline-recommended treatment option for these patients. The idea is to confirm what we saw in the PROSPECT study and show the superiority [of tirabrutinib] over a guideline-recommended and fairly frequently used regimen,” Grommes explained.

Eligible patients must be at least 18 years of age and have a pathologically confirmed diagnosis of relapsed/refractory PCNSL.¹ Patients must also have been treated with at least 1 prior methotrexate-based line of therapy, have a measurable brain lesion that is at least 1 cm in diameter, and have an ECOG performance status of 0 to 2. If patients have non–B-cell PCNSL, systemic presence of lymphoma, temozolomide-refractory disease, spinal PCNSL, or isolated intraocular PCNSL, they will not be included in the trial.

Patients in the trial will be randomly assigned in a 2:1 fashion to receive tirabrutinib, or rituximab plus temozolomide. Patients in the tirabrutinib arm will receive the agent orally at 480 mg daily until disease progression, unacceptable toxicities, or withdrawal of consent. Conversely, patients in the rituximab-plus-temozolomide arm will receive intravenous rituximab at 375 mg/m² on day 1 of each cycle and 150 mg/m² of oral temozolomide on days 1 to 5 of each cycle. Patients in the rituximab-plus-temozolomide arm will receive treatment for up to 6 cycles or until disease progression, unacceptable toxicities, or withdrawal of consent.

PFS per blinded independent central review (BICR) serves as the primary end point of IGNITE, with ORR per BICR, overall survival, and CR rate serving as key secondary end points.

What may be the clinical significance of positive data from IGNITE and a potential FDA approval of tirabrutinib for relapsed/refractory PCNSL?

“[IGNITE] is a confirmation of the PROSPECT study, thus it hopefully will not change the FDA’s view of [tirabrutinib]. [IGNITE may provide] an extra level of confirmation that BTK inhibitors [like tirabrutinib are] effective in this patient population. [IGNITE] will hopefully be positive, meaning [tirabrutinib] outperforms rituximab plus temozolomide, [leading] the FDA approval [to be granted], meaning we can use [tirabrutinib] even more,” Grommes pointed out.

“I love that we are shining a light on these patients with this rare illness who desperately need this attention,” Sumrall added. “The fact that the FDA is reviewing this NDA for tirabrutinib makes me feel encouraged that [the agent] 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 [therapies]. [Bringing] a well-tolerated, oral option to market for these patients [would] be a wonderful tool to have.”

Notably, positive data from IGNITE might also set the stage for the conduction of new clinical trials investigating treatments like CAR T-cell therapies, which are not often explored in the PCNSL field.

“The problem [following an FDA approval of tirabrutinib would be]: How do you integrate [tirabrutinib] with CAR T-cell therapy?” Grommes mentioned. “A trial concept [following an FDA approval might be] tirabrutinib as a bridging therapy to CAR T-cell therapy and then as maintenance afterwards. We might also find more data [from IGNYTE] predicting [which patients] might respond to a BTK inhibitor. Maybe [some of] those patients [could receive] CAR T-cell therapy rather than a BTK inhibitor. If the FDA approves tirabrutinib for relapsed or refractory [PCNSL], we see this [agent] moving forward into the first-line setting. Data have already been collected during PROSPECT in cohort B, where tirabrutinib was used with methotrexate-based chemotherapies upfront. We may see more moving of BTK inhibitors and CAR T-cell therapies into the first-line setting for PCNSL.”

Outside of BTK inhibition, what other treatments are being developed and evaluated for PCNSL?

Although positive data from IGNITE and the potential FDA approval of tirabrutinib for PCNSL would mark a milestone in improving outcomes and quality of life for patients, much remains to be discovered in the field, according to Grommes and Sumrall.

“[The PCNSL field is] learning as we go. We’re learning that some patients seem to respond better than others to CAR T-cell therapies; we’re not yet sure why. We’re doing a better job of identifying the biomarkers that are associated with different subtypes of lymphoma, which will inform our decisions as we move forward,” Sumrall said. “One unique challenge in this patient population is that we are treating patients with a cancer affecting the nervous system. CAR T-cell therapies and some other therapies [are associated with] unique neurologic AEs.”

Despite Sumrall’s concerns, Grommes believes that CAR T-cell therapies might not bring increased neurologic AEs to patients with PCNSL, but stressed logistical concerns about the accessibility of the treatment as an area of critical unmet need.

“There are not much data out there to tell which patients with PCNSL would benefit [from CAR T-cell therapy]. What we can say based on the data is that the [CAR T-cell therapy–related] toxicity we see in patients with PCNSL doesn’t differ from [that seen in patients] with non-CNS disease,” Grommes stressed. “The problem with CAR T-cell therapy, which is different from BTK inhibitors, is that you need to produce the CAR T cells: collect them, ship them, and treat the patient. [Manufacturing CAR T-cell therapy] takes a [relatively long time]. Some patients with PCNSL are in the relapsed or refractory setting and don’t have that time. In contrast, BTK inhibitors work quickly if they work; usually within 2 or 3 weeks we see clinical improvement. Maybe the idea is to combine [these 2 types of therapies] and find the sweet spot for those patients.”

Ultimately, the developments across the PCNSL field with multiple different treatment classes have given rise to an exciting time for research and disease management.

“Having so much excitement in the field is great. We rarely see [PCNSL] in neuro-oncology, and [now] we can [tell] patients [about the potential for] responses and cures. Everyone is excited to have the tools to be even more aggressive about treatment,” Grommes said.

“We’re seeing a rebirth of interest in [PCNSL]. We’re seeing compounds, such as BTK inhibitors, and there are also immunotherapy options, including CAR T-cell therapy, in this setting. It’s exciting to see my colleagues publish data on CAR T-cell therapy [that may help this type of agent gain approval for use] in clinical trials or in the commercial setting,” Sumrall concluded.

References

1. Nayak L, Grommes C, Psoinos C, et al. IGNITE: a phase III study of tirabrutinib versus rituximab and temozolomide combination therapy in relapsed/refractory primary central nervous system lymphoma. Future Oncology. Published online June 19, 2026. doi:10.1080/14796694.2026.2683574
2. 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
3. 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 17, 2026. Accessed June 22, 2026. https://www.deciphera.com/news/deciphera-pharmaceuticals-announces-us-food-and-drug-administration-acceptance-filing-new-drug