Genomic Determinants of Response and Resistance to Pirtobrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia.

Pirtobrutinib, a non-covalent, reversible Bruton tyrosine kinase inhibitor (BTKi), demonstrated efficacy in patients with chronic lymphocytic leukemia (CLL), resistant to covalent BTKi (cBTKi). Genomic correlations with response and resistance to pirtobrutinib were analyzed in relapsed/refractory (R/R) CLL patients pretreated with cBTKi and enrolled in the phase 1/2 BRUIN trial. DNA sequencing was performed on PBMCs at baseline, on treatment, and at progressive disease (PD). Common alterations at baseline included mutations in BTK (43%), TP53 (38%), SF3B1 (25%), NOTCH1 (23%), ATM (19%), XPO1 (11%), PLCG2 (9%), BCL2 (8%) and 17p deletion (28%). Common baseline BTK mutations included C481S (85%), C481R (10%), C481F (6%) and C481Y (4%). At PD, 60/88 patients (68%) acquired ≥1 mutation, including 44% with acquired BTK mutations and 24% with other acquired mutations. A total of 55 acquired BTK mutations were detected in 39 patients, including gatekeeper mutations (T474I/F/S/L/Y/P, 26%), kinase-impaired L528W (16%), C481F/R/Y (5%), V416L (2%), and A428D (1%) and others proximal to the ATP-binding pocket, D539G/H/A (1%) and Y545N (1%). Decrease or complete clearance of BTK C481x was observed at PD in 36/43 patients (84%). Using a more sensitive assay, 37% (18/49) of acquired BTK mutations were detected at baseline at low allele frequency. Using the highly sensitive assay at progression, a similar frequency of acquired BTK mutations (39%) was detected, and all patients had detectable acquired mutations. This study highlights the complex clonal dynamics of BTK mutations in R/R CLL patients undergoing pirtobrutinib treatment, and the extent of resistance without an obvious genomic driver. NCT03740529.