Results from the phase 1 study of the novel BCL2 inhibitor sonrotoclax (sonro) in combination
with zanubrutinib (zanu) for relapsed/refractory (R/R) CLL/SLL show deep and durable
responsesAuthors: Stephen Opat,1 Mary Ann Anderson,2 Alessandra Tedeschi,3 Emma Verner,4 Masa Lasica,5Alejandro Arbelaez,6 Stephan Stilgenbauer,7 Peter Browett,8 Sophie Leitch,9 Eva Gonzalez-Barca,10Mazyar Shadman,11 Jing-Zhou Hou,12 Herbert Eradat,13 Shuo Ma,14 David Westerman,2,15 YiqianFang,16 James Hilger,17 Sheel Patel,17 Wei Ding,17 Haiyi Guo,18 Constantine S. Tam19
Affiliations: 1Lymphoma Research Group, School of Clinical Sciences at Monash Health, Monash
University, Clayton, VIC, Australia; 2Peter MacCallum Cancer Center, Melbourne, VIC, Australia;
3ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; 4Concord Hospital, University ofSydney, Sydney NSW, Australia; 5St. Vincent’s Hospital Melbourne, Melbourne, VIC, Australia;
6Pindara Private Hospital, Benowa, QLD, Australia; 7Division of CLL, Internal Medicine III, Ulm

University, Ulm, Germany; 8Auckland City Hospital, Grafton, New Zealand; 9North Shore Hospital,Auckland, New Zealand; 10Institut Català d’Oncologia Hospitalet, Universitat de Barcelona, IDIBELL,Barcelona, Spain; 11Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 12University ofPittsburgh Medical Center, Pittsburgh, PA, USA; 13David Geffen School of Medicine, University ofCalifornia Los Angeles, Los Angeles, CA, USA; 14Robert H. Lurie Comprehensive Cancer Center,Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 15University of Melbourne,Melbourne, VIC, Australia; 16BeiGene (Beijing) Co, Ltd, Beijing, China; 17BeiGene USA, Inc, San
Mateo, CA, USA; 18BeiGene (Shanghai) Co, Ltd, Shanghai, China; 19Alfred Hospital and Monash
University, Melbourne, VIC, Australia
Background: Despite recent therapeutic advances, CLL/SLL remains incurable. The majority oftreated patients relapse, necessitating further treatment with novel agents. BCL2 inhibition is anestablished therapeutic strategy in CLL/SLL, and the addition of BTK inhibition is synergistic. Sonro(BGB-11417), a next-generation BCL2 inhibitor, is a more selective and potent inhibitor of BCL2 thanvenetoclax in biochemical assays. Zanu, a next-generation BTK inhibitor (BTKi), has shown improved
PFS and tolerability, including fewer cardiac AEs than ibrutinib in a randomized study of patients withR/R CLL/SLL and is approved for the treatment of CLL.
Aims: To report updated safety and efficacy data for patients with R/R CLL/SLL treated with sonro +zanu in the ongoing BGB-11417-101 (NCT04277637) study.
Methods: Patients with R/R CLL/SLL received zanu (320 mg QD or 160 mg BID) 8-12 wk before
starting sonro (40, 80, 160, 320, or 640 mg QD) with ramp-up to the target dose to mitigate potentialrisk of tumor lysis syndrome (TLS). Prior BTKi was allowed if disease progression occurred ontreatment. Patients were treated until disease progression or unacceptable toxicity. The primary
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endpoint was safety (per CTCAE v5.0); ORR (per iwCLL 2008 criteria) and minimal residual diseaseassessed in blood by ERIC flow every 24 weeks (uMRD4) were secondary and exploratory endpoints,respectively.
Results: As of Oct 31, 2023, 45 patients with R/R CLL/SLL were enrolled across different cohorts (40mg, n=4; 80 mg, n=9; 160 mg, n=6; 320 mg, n=20; 640 mg, n=6). Four patients were still in the zanu
lead-in phase and 41 had started sonro. The median age was 65 yrs (range, 36-76 yrs); 28% of tested
patients (11/40) had del(17p), and 72% (13/18) had unmutated IGHV. The median number of priortreatments was 1 (range, 1-3); 7 patients had prior BTKi as their last therapy. The median follow-up
was 17 months (range, 0.5-32.6 months). There were no DLTs; up to 640 mg, the MTD had not beenreached. Dose expansion was completed with a recommended phase 2 dose of 320 mg. Any-grade
treatment-emergent AEs (TEAEs) that occurred in ≥20% of patients were COVID-19 (n=12; 27%),contusion (n=12 [27%]), neutropenia (n=12 [27%]), diarrhea (n=11 [24%]), nausea (n=11 [24%]) andfatigue (n=11 [24%]). Neutropenia was the most common grade ≥3 TEAE (n=9 [20%]). No cases ofTLS or atrial fibrillation occurred; no TEAEs led to death, discontinuation, or dose reduction. Sonro
dose holds occurred in 14 patients for a median duration of 7 days, most commonly due to COVID-19(n=7). For 32 response-evaluable patients across all dose levels, the ORR was 97% (31/32; 1 patient[40 mg] had SD), and the complete response (CR) rate was 50% (40 mg, n=1 [25%]; 80 mg, n=4[50%]; 160 mg, n=4 [67%]; 320 mg, n=5 [56%]; 640 mg, n=2 [40%]). The median time to CR was 9.8months (range, 5.5-18.2 months). Of 4 response-evaluable patients with prior BTKi treatment, 3achieved PR (n=2) or CR (n=1). All patients treated with sonro + zanu (160 mg, 320 mg, or 640 mg)
who reached week 48 achieved uMRD4 (Figure). Treatment is ongoing for all but 1 patient in the 40
mg cohort who discontinued due to disease progression.
Conclusion: Efficacy of sonro + zanu combination treatment is encouraging, with a 97% ORR anddeep responses, including uMRD, in patients with R/R CLL/SLL. This combination has demonstrated
a tolerable safety profile across all dose levels tested.

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Figure. Best MRD by weeks 24 and 48

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