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
Year: 2025
Type: article
Abstract: 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.
Authors: L. Scarfò, R.D. Parrondo, M.C. Thompson, A.M. Frustaci, J.N. Allan, P. Ghia, I. Mocanu, C.S. Tam, S. Stilgenbauer, D. Roos-Weil, J. Trotman, I. E. Ahn, N. Lamanna, L. Xu, K. By, S. Fabre, D. Persky, A. Agarwal, J. F. Seymour
Institutions: Vita-Salute San Raffaele University, IRCCS Ospedale San Raffaele, Mayo Clinic, Mayo Clinic in Florida, Memorial Sloan Kettering Cancer Center, Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda, Weill Cornell Medicine, The Alfred Hospital, Monash University, Universität Ulm, Pitié-Salpêtrière Hospital, The University of Sydney, Concord Repatriation General Hospital, Dana-Farber Cancer Institute, Herbert Irving Comprehensive Cancer Center, Columbia University, The Royal Melbourne Hospital, The University of Melbourne, Peter MacCallum Cancer Centre
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7093121614
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