Primary central nervous system lymphoma (PCNSL) is an aggressive B-cell malignancy of the brain, spinal cord, cerebrospinal fluid, or eyes. High-dose methotrexate-based chemotherapy anchors initial treatment, yet up to 30% of patients are refractory and many initial responders relapse.
In the phase 2 PROSPECT trial, the second-generation Bruton tyrosine kinase (BTK) inhibitor tirabrutinib gave rapid, frequent responses in relapsed or refractory disease. Responses were often temporary, and a fatal fungal infection showed that greater kinase selectivity doesn’t remove infection risk. PROSPECT is the largest prospective evaluation of tirabrutinib at its recommended dose in this population and extends earlier experience from Asia, where the drug is approved for relapsed or refractory PCNSL.
BTK Inhibition in PCNSL
Salvage is hardest in older patients and in those with neurological impairment, prior intensive chemotherapy, or limited transplant eligibility. PCNSL frequently depends on abnormal B-cell receptor signaling and activation of the nuclear factor kappa-B pathway. BTK inhibition interferes with these survival signals, and small-molecule BTK inhibitors penetrate the central nervous system.
The first-generation inhibitor ibrutinib produced overall response rates of about 52%-77% in relapsed or refractory PCNSL, but responses lasted a median of about six months, and bleeding, atrial fibrillation, and fungal infections complicated treatment. Tirabrutinib is more selective and was developed to preserve antitumor activity while reducing off-target toxicity. Japanese studies supported its approval in Japan, South Korea, and Taiwan.
Trial Design and Patients
PROSPECT (NCT04947319) is a multicenter, open-label, phase 2 study. Part A enrolled 48 adults at 20 US centers whose PCNSL had relapsed or progressed after at least one high-dose methotrexate-based regimen. Patients received oral tirabrutinib 480 mg once daily, fasting, until progression or unacceptable toxicity.
The primary endpoint was overall response rate, assessed by an independent review committee using International PCNSL Collaborative Group criteria. Secondary endpoints were complete response rate, duration of response, time to response, corticosteroid use, and safety. Progression-free survival and overall survival were exploratory.
Median age was 65.5 years (range, 34-87). All patients had received high-dose methotrexate-based treatment, and 90% had received rituximab. Roughly half had relapsed disease and half had disease refractory to the most recent treatment, and most had one prior regimen. Prior BTK inhibitor exposure, poor performance status, and isolated ocular disease without a measurable brain lesion were exclusions.
Results: Rapid Responses, Limited Durability
At a median follow-up of 11.5 months, the trial met its primary endpoint. ORR was 67%, and the CR rate, including unconfirmed CRs, was 44%. Median time to response was 1.0 month. Speed matters in PCNSL, where neurological deterioration can be rapid and visual loss may become irreversible.
Median duration of response was 9.3 months. Among responders, the probability of maintaining response was 64% at six months, 43% at 12 months, and 28% at 18 months. Median PFS was 6.0 months, with 35% of patients progression-free at one year. Median OS was not reached, and estimated OS was 67% at 12 months.
The gap between response rate and PFS reflects frequent progression despite strong initial control: by November 2024, 26 patients had discontinued treatment because of progression, and only 13 of 48 remained on therapy. The 9.3-month median duration of response compares favorably with roughly 5.5-6.3 months in earlier ibrutinib monotherapy studies. These are indirect comparisons across separate trials.
Corticosteroid Reduction
Among 16 patients receiving corticosteroids at baseline, 81% achieved a sustained dose reduction of at least 50%, and 69% met the study definition of corticosteroid discontinuation. This matters because prolonged corticosteroid exposure contributes to infections, hyperglycemia, muscle weakness, osteoporosis, and thromboembolism, particularly in older patients. The definition required a steroid-free period lasting at least 25% of the duration of tirabrutinib treatment, so it doesn’t necessarily indicate permanent discontinuation.
Subgroups
ORR was 77% in relapsed disease and 61% in refractory disease. By age ORR was:
- 58% below 65 years
- 56% at 65 to under 75 years
- 92% at 75 years or older
The oldest group had only 13 patients, so the result doesn’t show that older age predicts greater sensitivity. In exploratory genomic analysis of 24 patients, responses occurred across MYD88, CD79B, and PIM1 mutations. Three of five patients with CARD11 mutations responded, which is notable because activating CARD11 alterations have been associated with BTK inhibitor resistance. Small numbers and the absence of a comparator preclude conclusions about predictive value.
Safety
Adverse events were treatment-related in 75% of patients, with grade 3 or higher treatment-related events in 27%. The most frequent were anemia, maculopapular rash, fatigue, neutropenia, lymphocytopenia, and pruritus, each in 15%-19%. Adverse events led to dose interruption in 50% of patients, dose reduction in 10%, and permanent discontinuation in 10%.
Cardiac events occurred in 8%, all grade 1 or 2, and no atrial fibrillation occurred. This is relevant given the cardiovascular toxicity of less selective BTK inhibitors, though the small sample can’t exclude the risk. Bleeding occurred in 25%. Two patients had grade 3 or higher intracranial hemorrhage, neither considered treatment-related. One patient developed Stevens-Johnson syndrome.
Fungal Infection
One death from bronchopulmonary aspergillosis was considered treatment-related, occurring 57 days after tirabrutinib discontinuation. The patient had received antiviral and antibacterial prophylaxis but no antifungal prophylaxis. Invasive fungal infections have been reported with other BTK inhibitors in PCNSL, and prior chemotherapy, corticosteroids, neurological disability, and immunosuppression add risk.
Only 40% of participants received antimicrobial or antifungal prophylaxis. The study recommended antifungal prophylaxis for anticipated profound, prolonged neutropenia and antimicrobial prophylaxis for patients on corticosteroids. The absence of atrial fibrillation and the low rate of severe treatment-related events are reassuring.
Comparison With Other BTK Inhibitors
Earlier ibrutinib monotherapy studies reported median PFS generally under five months. In the phase 2 PRiZM+ study, zanubrutinib monotherapy produced an ORR of 55% and median PFS of 6.9 months. A separate study of zanubrutinib with cytarabine reported an ORR of 65%. Tirabrutinib’s efficacy was broadly consistent with Japanese studies, postmarketing surveillance, and compassionate use in Taiwan, where response rates ranged from about 61% to 75%.
Role Alongside CAR T-Cell Therapy
The primary CNS lymphoma limitation was removed from the US prescribing information for axicabtagene ciloleucel, an anti-CD19 CAR T-cell therapy. CAR T-cell therapy requires specialized centers, manufacturing time, and careful management of neurological toxicity, and some patients progress rapidly while waiting.
An oral therapy available immediately and capable of responses within about one month could help in selected patients who need rapid disease control. The investigators propose BTK inhibitors as bridging before CAR T-cell therapy or as maintenance afterward.
Limitations and Perspective
The single-arm design is the principal limitation: without randomization or an active comparator, the trial can’t show whether tirabrutinib improves survival over existing salvage therapies or has a better safety profile than other BTK inhibitors.
The cohort was small, and median follow-up of 11.5 months is too short to establish the durability of CRs or late adverse events. Exclusion of prior BTK inhibitor exposure, poor performance status, and isolated ocular disease limits generalizability. The randomized phase 3 IGNITE trial (NCT07104032) is expected to give more definitive evidence. Randomized data are also needed on sequencing and integration with other therapies.
Source: Grommes C, Nayak L, et al. Efficacy and safety of tirabrutinib monotherapy for relapsed/refractory primary CNS lymphoma: PROSPECT phase 2 trial. Blood. 2026. ClinicalTrials.gov: NCT04947319.
