Pirtobrutinib, a highly selective, noncovalent Bruton’s tyrosine kinase (BTK) inhibitor, was shown to be effective in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who were resistant to covalent BTK inhibitors. Researchers evaluated genomic mechanisms of pirtobrutinib resistance in patients with CLL or SLL who had previously received covalent BTK inhibitors, noting that causes of pirtobrutinib resistance had not been systematically investigated.
According to their report, presented at the European Hematology Association 2023 Hybrid Congress, patients who progressed on pirtobrutinib commonly showed clearance of BTK C481 clones as well as new or increased non-C481 clones, especially gatekeeper T474 and kinase-impaired L528W mutations, among other variants of unknown significance (VUS).
Researchers also observed many acquired BTK mutations were present at baseline with low variant allele frequency (VAF), suggesting they occurred during prior covalent BTK inhibitor therapy. Notably, these mutations did not predict pirtobrutinib resistance. In fact, approximately half of patients who progressed on pirtobrutinib did not acquire BTK mutations, and 29% did not acquire any mutations, indicating alternative mechanisms of resistance.
Genetic Mutations in CLL Don’t Predict Response
The analysis included 49 patients with CLL and previous covalent BTK inhibitor treatment who received pirtobrutinib monotherapy in the phase 1/2 BRUIN trial and subsequently experienced disease progression. Targeted next-generation sequencing (NGS) was performed on peripheral blood mononuclear cells collected at enrollment and at or near progression.
The cohort had a median age of 69 years (range, 36-86 years), a median of 4 prior lines of therapy (range, 1-10 lines), and 41 (84%) patients had discontinued covalent BTK inhibitors due to disease progression. The overall response rate for pirtobrutinib was 80%
The most common baseline mutations were in BTK (51%), TP53 (49%), ATM (27%), NOTCH1 (20%), SF3B1 (18%), and PLCG2 (10%). Among 25 patients with 1 or more BTK alterations at baseline, mutations included BTK C481S (n=23), C481R (n=4), C481Y (n=2), C481F (n=1), and T474I (n=1). Researchers noted a decrease or complete clearance of BTK C481 VAF at time of disease progression in 92% of patients (n=22).
NGS of samples collected at progression showed 35 of 49 (71%) patients had acquired 1 or more mutations, and 27 of 49 (55%) had acquired 1 or more BTK mutations. Among those 27 patients, researchers identified 36 acquired BTK mutations.
The most common acquired BTK mutations at progression were gatekeeper T474I/F/L/Y (17 of 49; 35%), kinase-impaired L528W (9 of 49; 18%), and VUS proximal to the adenosine triphosphate-binding pocket (6 of 49; 12%), including V416L (n=2), A428D (n=2), D539G/H (n=1), and Y545N (n=1). The most common non-BTK mutations were TP53 (7 of 49; 14%) and PLCG2 (4 of 49; 8%).
The researchers summarized that pretreated patients with CLL or SLL who experienced disease progression while on pirtobrutinib showed some similar genomic evolutions, but these were unlikely the only underlying mechanisms of pirtobrutinib resistance. “Whether similar patterns of resistance would manifest if pirtobrutinib was utilized in earlier lines of therapy or prior to [covalent BTK inhibitor] treatment remains uncertain,” they closed.
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