C056 | UPDATED EFFICACY/SAFETY OF THE BRUTON TYROSINE KINASE DEGRADER BGB-16673 IN RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA: RESULTS FROM THE ONGOING PHASE (PH) 1 CADANCE-101 STUDY

BACKGROUND: BGB-16673, a potential first-in-class protein degrader, blocks BTK signaling by tagging BTK for degradation through the cell's proteasome pathway. Updated ph 1 results in R/R CLL/SLL from open-label CaDAnCe-101 (BGB-16673-101; NCT05006716) are reported. METHODS: Patients (pts) with ≥2 prior treatments (txs; including a covalent BTK inhibitor [cBTKi] in US/EU/Australia) received BGB-16673 QD orally. Endpoints included safety, maximum tolerated dose, recommended dose for expansion, and ORR (modified iwCLL 2018 criteria; 2014 Lugano criteria in SLL). RESULTS: As of 17Dec2024, 66 pts were enrolled and treated (50 mg-500mg). Median age was 70 y (range, 47-91); 65.2% (43/66) had del(17p) and/or TP53 mutation; 79.6% (39/49) had unmutated IGHV. Pts had a median of 4 prior txs (range, 2-10), including cBTKis (n=61; 92.4%), BCL2 inhibitors (BCL2is; n=54; 81.8%), and noncovalent BTKis (ncBTKis; n=14; 21.2%). Median follow-up was 13.1 months (m; range, 0.3-29.9). TEAEs in ≥30% were fatigue (36.4%; grade [gr] ≥3, 1.5%) and contusion/bruising (30.3%; no gr ≥3). Most common gr ≥3 TEAE was neutropenia/neutrophil count decreased (21.2%). Atrial fibrillation (gr 1 in the context of bacterial pneumonia) and febrile neutropenia (in the context of COVID-19 pneumonia and norovirus diarrhea) occurred in 1 pt (1.5%) each. Hypertension (gr 3, n=2) and major hemorrhage (gr 1, n=1; gr 3, n=1) occurred in 2 pts (3.0%) each. TEAEs led to dose reductions in 6 pts (9.1%) and 4 deaths. In evaluable pts, ORR (partial response with lymphocytosis [PR-L] or better) was 80.3% (53/66; 2 complete response [CR]/CR with incomplete marrow recovery [CRi; 3.0%]). ORR at 200mg was 93.8% (15/16; 1 CR). Median time to first response was 2.8 m (range, 2.0-10.9); 33 pts (50.0%) remained on tx for ≥12 m; 38 had ongoing responses. Of 19 pts with initial PR-L, 10 improved to PR and 1 to CR; of 15 pts with stable disease, 1 improved to PR-L, 5 to PR, and 1 to CRi. Responses occurred in pts with prior cBTKi (49/61; 80.3%) or ncBTKi (10/14; 71.4%); double- (cBTKi and BCL2i; 36/41; 87.8%) and triple-exposure (cBTKi, BCL2i, ncBTKi; 9/12; 75.0%); del(17p) and/or TP53 mutation (33/43; 76.7%); with (17/24; 70.8%) and without (33/39; 84.6%) BTK mutations, and at the lowest dose (50 mg, 1/1). Median PFS was not reached. CONCLUSIONS: Novel BTK degrader BGB-16673 is tolerable, with robust and deepening responses in pts with heavily pretreated R/R CLL/SLL, including pts with prior BTKis and BTKi mutations.