DP006 | UPDATED SAFETY AND EFFICACY RESULTS OF A PHASE-1 STUDY OF THE NOVEL BCL2 INHIBITOR SONROTOCLAX (SONRO; BGB-11417) FOR RELAPSED/REFRACTORY WALDENSTRÖM MACROGLOBULINEMIA

BACKGROUND: Sonro (BGB-11417), a next-generation BCL2 inhibitor, is more selective and a more pharmacologically potent inhibitor of BCL2 than venetoclax, with a shorter half-life and no drug accumulation. Sonro monotherapy is being studied in the dose-escalation part of the ongoing BGB-11417-101 (NCT04277637) study in B-cell malignancies; here, updated safety/efficacy data for R/R WM are presented. METHODS: Pts with WM (≥1 prior treatment [tx]) received sonro via target dose ramp-up (80, 160, 320, or 640mg QD) and were treated until progression/unacceptable toxicity. The primary endpoint is safety; a secondary endpoint is overall response rate (ORR; minor response [MR] or better, modified Owens 2013 criteria). Tumor lysis syndrome (TLS) was assessed per Howard 2011 criteria. RESULTS: As of 6Dec2024, a total of 23 pts with R/R WM were enrolled in 4 dose-escalation cohorts (80 mg, n=6; 160 mg, n=8; 320 mg, n=5; 640 mg, n=4). The median number of prior tx was 3 (range, 1-9); 14 pts received prior BTK inhibitor (BTKi; noncovalent, n=1; covalent, n=13) tx and 22 had prior anti-CD20. Median follow-up was 18.6 mo (range, 2.1-37.2). Nine pts discontinued tx: 6 due to progressive disease (PD) and 3 due to tx-emergent adverse events (TEAEs; multifocal neurological syndrome, COVID-19 pneumonia, and hemolysis [tx-related]). Six pts died on study due to PD (n=4), COVID-19 pneumonia (n=1), and pneumonia (n=1); none were tx-related. TEAEs in ≥20% of pts were anemia (34.8%), COVID-19 (34.8%), and neutropenia, nausea, and pyrexia (21.7% each). Anemia was the most common grade ≥3 TEAE (21.7%). No TLS occurred with tested doses ≤640 mg. No atrial or ventricular fibrillation occurred. In 23 evaluable pts, the overall (ORR), major (MRR; partial response [PR] or better), and very good PR (VGPR) rates were 78.3%, 60.9%, and 13.0%, respectively. With a median follow-up of 22.1 mo (range, 11.2-24.0), median progression-free survival was not reached (95% CI, 19.7-NE) (Figure). Nine pts with a BTKi as their last tx had an ORR of 66.7% (MR, n=1; PR, n=4; VGPR, n=1). In the 320mg cohort, with a median follow-up of 14.2 mo (range, 12.8-18.6), all pts responded and had an MRR of 80% (1 VGPR). CONCLUSIONS: Sonro monotherapy is tolerable across tested doses and has encouraging antitumor activity, with ORRs of 78.3% across dose levels and 100% at sonrotoclax RP2D (320mg) in heavily pretreated WM. Further evaluation of sonro monotherapy in R/R WM is ongoing in a potentially pivotal phase 2 study.