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

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.