C092 | UPDATED EFFICACY AND SAFETY OF THE BRUTON TYROSINE KINASE DEGRADER BGB-16673 IN PATIENTS WITH RELAPSED/REFRACTORY WALDENSTRÖM MACROGLOBULINEMIA: ONGOING PHASE-1 CADANCE-101 STUDY RESULTS

BACKGROUND: BGB-16673 is a potential first-in-class protein degrader that blocks BTK signaling by tagging BTK for degradation through the cell's proteasome pathway. Updated ph 1 results in WM from the ongoing, open-label, ph 1/2 CaDAnCe-101 (BGB-16673-101; NCT05006716) are presented. METHODS: Pts with ≥2 prior WM treatments (tx), including an anti-CD20 antibody and covalent BTK inhibitor (cBTKi; US/EU only), received BGB-16673 QD orally. Endpoints included safety and tolerability (CTCAE v5.0), maximum tolerated dose, recommended dose for expansion, and overall response rate (ORR; modified IWWM-6 criteria) beginning after 4 weeks of tx. RESULTS: As of 17Dec2024, 30 pts with WM were enrolled and treated (100mg-350mg). Median age was 72.5 y (range, 56-81). Median number of prior tx was 3 (range, 2-11), including cBTKis (100%), BCL2 inhibitors (23.3%), and noncovalent BTKis (ncBTKis; 13.3%). Mutations in BTK (37.9%, 11/29) and TP53 (51.7%, 15/29) were seen. Median follow-up was 8.1 months (m; range, 0.3-28.1). TEAEs in ≥20% of pts were neutropenia/neutrophil count decreased (43.3%), diarrhea (30.0%), contusion/bruising (26.7%), anemia (23.3%), pyrexia (20.0%), and thrombocytopenia (20.0%). The most common grade [gr] ≥3 TEAE was neutropenia/neutrophil count decreased (33.3%). No atrial fibrillation, febrile neutropenia, or major hemorrhage occurred. Gr 2 hypertension was seen in 1 pt. Five pts (16.7%) had a gr ≥3 infection. TEAEs led to discontinuation (d/c) in 1 and dose reduction in 2 pts. One pt died due to a TEAE; 1 died of progressive disease (PD). In 29 evaluable pts, overall, major, and very good partial response rates were 89.7%, 75.9%, and 31.0%, respectively. Median time to first response was 0.95 m (range, 0.9-3.9), and median time to major response was 1.9 m (range, 0.9-6.4); responses deepened over time. Twenty-two pts (73.3%) remain on tx with ongoing responses. Responses were seen at the lowest dose (100 mg, 10/10), in cBTKi- (26/29) and ncBTKi-treated pts (4/4), and in pts with prior BTKi d/c due to PD (21/23). Responses were independent of mutations in BTK (with [w], 11/11; without [wo], 14/17), MYD88 (w, 23/25; wo, 2/3), CXCR4 (w, 14/14; wo, 11/14), and TP53 (w, 15/15; wo, 10/13). Median PFS was not reached. CONCLUSIONS: In this ongoing study, the novel BTK degrader BGB-16673 is tolerable and continues to show substantial antitumor activity in pts with heavily pretreated, BTKi–exposed WM, including those with BTK, CXCR4, and TP53 mutations.