Key clinical point: A phase 1 trial of the next-generation BTK inhibitor LOXO-305 has demonstrated safety and provided evidence of its efficacy in heavily pretreated patients with B-cell malignancies.
Major finding: The overall response rate was 77% for chronic lymphocytic leukemia and 50% for mantle cell lymphoma.
Study details: A phase 1 trial (BRUIN) involving 28 adult patients with B-cell malignancies.
Disclosures: Dr. Mato reported disclosures related to Gilead, Pharmacyclics, AstraZeneca, AbbVie, Sunesis, Johnson & Johnson, TG Therapeutics, LOXO, DTRM Biopharma, Genentech, Janssen, Acerta, Pharmacyclics, and Celgene.
Mato AR et al. ASH 2019, Abstract 501.
Unlike the FDA-approved BTK inhibitors ibrutinib, acalabrutinib, and zanubrutinib, LOXO-305 is a non-covalent, reversible inhibitor of BTK. The BTK C481S mutation prevents covalent inhibitors from binding to BTK and are associated with treatment failure. A well tolerated drug with activity in wildtype and mutant BTK could be a significant improvement in care for patients with CLL, although the impact is likely to be less in MCL and other lymphomas that primarily employ different mechanisms of resistance. Will we soon see new BTK mutations that impact non-covalent BTK inhibitors?—Peter Martin, MD