Evolution of the BTK Inhibitor Class and Comparative Tolerability

Dr. Lakshmi Nayak transitions the discussion to the evolution of the BTK inhibitor class, the program's second module. Dr. Christian Grommes traces the class from ibrutinib, the first-in-human, first-generation covalent BTK inhibitor, through second-generation covalent agents (acalabrutinib, zanubrutinib) engineered for greater selectivity and improved tolerability, to non-covalent agents such as pirtobrutinib, developed to overcome the C481S resistance mutation observed in CLL but not typically identified in PCNSL. He frames tirabrutinib as a highly selective, irreversible second-generation BTK inhibitor evaluated specifically in PCNSL and approved in Japan, South Korea, and Taiwan, and reviews the U.S. regulatory pathway: the completed Phase 2 PROSPECT study now under FDA review, and an ongoing Phase 3 trial comparing tirabrutinib monotherapy with NCCN-recommended rituximab plus temozolomide. He notes that BTK inhibitors are generally well tolerated aside from bleeding, atrial fibrillation, and fungal infection risk, the last lacking consensus prophylaxis guidance. Dr. Chieh-Lung Cheng reinforces the same class evolution, emphasizing reduced off-target toxicity (arrhythmia, atrial fibrillation, hypertension) with newer agents, and noting that pirtobrutinib is FDA-approved for relapsed/refractory CLL and mantle cell lymphoma after covalent BTK inhibitor failure but is not approved in Taiwan.