Covalent Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL2) inhibitors are standard of care for most patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). However, resistance to covalent BTK inhibitors may develop over time, and BCL2 inhibitors have a limited duration of disease control. After progressing on a covalent BTK inhibitor and a BCL2 inhibitor, therapeutic options are limited and outcomes are poor.
Noncovalent BTK inhibitors may address unmet needs in this population. A phase 1/2 trial demonstrated the efficacy of pirtobrutinib, a noncovalent BTK inhibitor, in heavily pretreated patients with CLL or SLL (NCT03740529). In this trial, 247 patients with relapsed/refractory CLL or SLL had received at least 1 prior BTK inhibitor; of these, 40.5% had also received a BCL2 inhibitor. Most (76.9%) patients discontinued prior BTK inhibitor therapy due to disease progression.
The overall response rate (ORR) was 73.3% (including 4 complete responses, 1 nodular partial response, and 176 partial responses) in the prior BTK inhibitor subgroup. In the prior BTK/BCL2 inhibitor subgroup, the ORR was 70.0%. Median progression-free survival rates were 22.1 and 16.8 months in the prior BTK inhibitor and prior BTK/BCL2 inhibitor subgroups, respectively. Only 2.8% of patients discontinued the study drug due to a treatment-related adverse event.
Nemtabrutinib, another noncovalent BTK inhibitor, also shows promising activity in pretreated CLL or SLL and is under clinical development ( NCT04728893).
Are you convinced by the evidence for noncovalent BTK inhibition in CLL/SLL? Do you need additional data before incorporating it into treatment plans?
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Sanjaykumar Hapani, MERCY HOSPITAL OKLAHOMA CITY, INC1yrI agreeem with comments above
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Eric Schaefer1yrI think based on phase I/II data there were clear response rates. Would like to see data from confirmatory trial. I would also likely use a BCL2 before Show More
