S146: GENOMIC EVOLUTION AND RESISTANCE TO PIRTOBRUTINIB IN COVALENT BTK-INHIBITOR (CBTKI) PRE-TREATED CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) PATIENTS: RESULTS FROM THE PHASE I/II BRUIN STUDY

• DOI: 10.1097/01.hs9.0000967496.62332.46
• Publication Date: 2023-08-08T13:02:35Z
• Authors: Jennifer R. Brown; Sai Prasad Desikan; Bastien Nguyen; Helen Won; Shady Tantawy; Samuel Clark Mcneely; Narasimha Marella; Kevin Ebata; Jennifer Woyach; Krish Patel; Constantine Tam; Toby Eyre; Chan Cheah; Nirav N Shah; Paolo Ghia; Wojciech Jurczak; Minna Balbas; Binoj Nair; Paolo Abada; Chunxiao Wang; Denise Wang; Anthony R. Mato; Varsha Gandhi; William G. Wierda
• Keywords: Oral Sessions; Diseases of the blood and blood-forming organs; RC633-647.5

Background: Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, demonstrated broad efficacy in patients (pts) with CLL/SLL who were resistant to cBTKi. Mechanisms of resistance pirtobrutinib have not been systematically analyzed date. Aims: To explore the genomic evolution cBTKi pre-treated pts. Methods: CLL pts treated monotherapy phase 1/2 BRUIN trial (NCT03740529) subsequently developed disease progression (PD) included this analysis. Targeted next-generation sequencing (NGS) all exons 74 relevant genes was centrally performed on peripheral blood mononuclear cells collected at baseline and or near PD. Somatic mutations reported limit detection (LoD) 5% variant allele frequency (VAF). Manual inspection BTK LoD 1% detect whether identified PD present <5% VAF. Results: As 29 July 2022, 49 progressed had paired NGS data available In group, median age 69 y (range, 36-86), number prior lines 4 1-10), 41 (84%) discontinued due Pts received one more following cBTKi: ibrutinib (n=44, 90%), acalabrutinib (n=10, 20%), zanubrutinib (n=1, 2%). The ORR (including PR-L) 80%. most common alterations (51%), TP53 (49%), ATM (27%), NOTCH1 (20%), SF3B1 (18%), PLCG2 (10%). Among 25 ≥1 mutation detected baseline, C481S (n=23), C481R (n=4), C481Y (n=2), C481F (n=1), T474I (n=1). C481 VAF decrease complete clearance observed nearly (92%, 22/24, =100%). samples showed 71% (35/49) acquired mutation, 55% (27/49) acquiring mutation. these 27 pts, total 36 identified; gatekeeper (T474I/F/L/Y, 17/49, 35%), kinase-impaired (L528W, 9/49, 18%), variants unknown significance (VUS) proximal ATP-binding pocket (6/49, 12%; including V416L A428D D539G/H Y545N (n=1)) (figure). for corresponding revealed that 9 (in 8 pts) pre-existed low VAFs (1-4%). These 6 T474I/L, 2 kinase impaired L528W, 1 VUS A428D. responded (6/8, 75% ORR) (n=5) (n=4). commonly non-BTK (7/49, 14%) (4/49, 8%). Summary/Conclusion: clones emergence outgrowth non-C481 clones, particularly T474 L528W mutations, as well other VUS. Many shown pre-exist VAF, reflecting Importantly, domain did preclude efficacy. Approximately half acquire 29% any targeted panel, suggesting alternate mechanisms. Whether similar patterns would manifest if utilized earlier therapy treatment remains uncertain.Keywords: Molecular markers, Chronic lymphocytic leukemia, Genomics, Bruton’s tyrosine inhibitor (BTKi)