ICML 2025 | The Phase II PROSPECT trial: the efficacy and safety of tirabrutinib in R/R primary CNS lymphoma

The PROSPECT phase 2 trial is evaluating the role of the second-generation, highly potent BTK inhibitor tirabrutinib in relapsed and refractory primary CNS lymphoma. As we all know that the B-cell receptor signaling pathway and the toll-like receptor signaling pathway are active in high-grade lymphomas and particularly in primary CNS lymphoma, this is a very novel and potent agent evaluating its efficacy in this area of unmet need. So in this study, we investigated the role of tirabrutinib in 48 patients with relapse and refractory primary CNS lymphoma. This was a heavily pre-treated population, approximately 48% of patients were refractory to their primary treatment that they had received. And this patient population can be quite challenging to treat as they fail to respond to the next line of therapy compared to the recurrent patients. Every patient had previously received high-dose methotrexate-based chemotherapy. A fraction of patients had also received high-dose chemotherapy with autologous transplant and whole-brain radiation as well. In this study, remarkably, we found that the objective response rate was 67% and the complete response rate was 44%. And then importantly, when we think about the role of BTK inhibitors in primary CNS lymphoma, one question is durability. And we found that there was an impressive durability of response with this next-generation BTK inhibitor, and the median duration of response to this agent was nine months. The median progression-free survival for the entire cohort was six months, and the median overall survival has not been reached. So based on these results, we’re very excited about the potential of tirabrutinib as an agent for relapse and refractory primary CNS lymphoma. One other thing is that the toxicity of BTK inhibitors is something that we always like to think about and consider, especially in our population, which sometimes can be elderly and is heavily pretreated, so they’re already recovering from side effects of other agents and especially myelotoxic therapies as well. And remarkably, we found that this was very well tolerated. And when you think about BTK inhibitors, we did not really see very severe cardiac events. And in fact, we noted no events of atrial fibrillation in this population. With regard to skin toxicities, these were quite well managed as well. And so were other toxicities, mostly grade 1 and 2.

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