C036 | Sonrotoclax (sonro; Bgb-11417), a Novel Bcl2 Inhibitor, Plus Zanubrutinib Demonstrates Deep and Durable Responses in Relapsed/refractory Cll/sll: Updated Phase-1 Results
Year: 2025
Type: article
Abstract: BACKGROUND: Sonro (BGB-11417), a next-generation BCL2 inhibitor (BCL2i), is a more selective and pharmacologically potent inhibitor of BCL2 than venetoclax. ZANUBRUTINIB (zanu) a next-generation BTK inhibitor (BTKi), is highly effective in CLL with superior PFS and fewer cardiac AEs vs ibrutinib in pts with R/R CLL/SLL. Updated data for sonro + zanu in R/R CLL/SLL in the ongoing BGB-11417-101 (NCT04277637) study are presented. METHODS: Pts received zanu (320 mg QD/160mg BID) 8-12 wk before starting sonro with target dose ramp-up (40-640 mg QD). Pts with prior progression on a BTKi or BCL2i exposure were excluded from the cohort. Pts were treated until progression/unacceptable toxicity. The primary endpoint was safety; additional endpoints were ORR per iwCLL 2018 criteria and undetectable measurable residual disease in blood by standardized ERIC flow every 24 wk (uMRD4). RESULTS: As of 6 Dec 2024, 47 pts with R/R CLL/SLL were enrolled and received combination tx; of tested pts, 26.2% (11/42) had del(17p) and 73.2% (30/41) had unmutated IGHV. Median number of prior tx was 1 (range, 1-3); 7 pts had a BTKi as their last tx. Median follow-up was 29.4 mo (range, 10.2-45.8). No DLTs occurred; sonro MTD was not reached with doses ≤640 mg. Dose expansion was completed; RP2D was 320 mg. The most common any-grade tx-emergent AE (TEAE) was COVID-19 (36.2%). Neutropenia was the most common grade ≥3 TEAE (27.7%; no febrile events). No tumor lysis syndrome occurred. TEAEs led to 4 (8.5%) discontinuations (d/c; myelodysplastic syndrome, meningococcal sepsis, plasma cell myeloma, and intracranial hemorrhage [zanu d/c only]). No TEAEs led to death. In 46 evaluable pts, ORR was 95.7% (SD, n=2); complete response (CR) rate was 50.0%. Median time to CR was 10.2 mo (range, 5.3-42.4). Of 7 evaluable pts with prior BTKi, 6 achieved PR (n=5) or CR (n=1). Of 45 MRD-evaluable pts, 80.0% achieved uMRD4, with evidence of responses deepening over time. All 14 pts treated with sonro 160, 320, or 640mg + zanu who reached wk 96 achieved uMRD4 (Figure). One pt converted from uMRD to MRD4+ 6 mo after elective tx d/c and still remained in CR. With median follow-up of 29.4 mo, only 2 PFS events occurred (40 mg, n=1; 320 mg, n=1); 24-mo PFS rate was 94.5%. CONCLUSIONS: Sonro + zanu demonstrated a tolerable safety profile across all doses tested. Antitumor activity of this combination is encouraging, with a 95.7% ORR, deep responses, and uMRD observed in pts with R/R CLL/SLL, including those with previous BTKi tx.
Authors: A. Tedeschi, C.Y. Cheah, C.S. Tam, M.A. anderson, E. Verner, M. Lasica, A. Arbelaez, S. Stilgenbauer, P. Browett, S. Leitch, E. González-Barca, M. Shadman, J-Z. Hou, H. Eradat, D. Westerman, Y. Fang, J. Hilger, S. Patel, S.S. Opat
Institutions: Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda, The University of Western Australia, Sir Charles Gairdner Hospital, Linear Clinical Research, The Alfred Hospital, Monash University, The Royal Melbourne Hospital, Walter and Eliza Hall Institute of Medical Research, Peter MacCallum Cancer Centre, The University of Sydney, Concord Repatriation General Hospital, St Vincent's Hospital Melbourne, Universität Ulm, Auckland City Hospital, Health New Zealand, Institut d'Investigació Biomédica de Bellvitge, Institut Català d'Oncologia, Universitat de Barcelona, University of Washington, Fred Hutch Cancer Center, University of Pittsburgh Medical Center, University of California, Los Angeles, The University of Melbourne, Monash Health
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7093121929
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