Combination of zanubrutinib + venetoclax for treatment-naive (TN) CLL/SLL withdel(17p) and/or TP53: preliminary results from SEQUOIA arm DShuo Ma,1 Talha Munir,2 Masa Lasica,3 Mazyar Shadman,4 Alessandra Tedeschi,5Emmanuelle Ferrant,6 Ian W. Flinn,7 Wojciech Janowski,8 Monica Tani,9 Tadeusz Robak,10Jennifer R. Brown,11 Constantine Tam,12,13 Tian Tian,14 Emily Mantovani,14 StephanieAgresti,14 Linlin Xu,14 Alieen Cohen,14 Wojciech Jurczak,15 Paolo Ghia16,171Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School ofMedicine, Chicago, IL, USA; 2St James's Hospital, Leeds Teaching Hospitals NHS Trust,Leeds, UK; 3St Vincent's Hospital, Melbourne, VIC, Australia; 4Fred Hutchinson Cancer
Research Center, Seattle, WA, USA; 5ASST Grande Ospedale Metropolitano Niguarda,Milan, Italy; 6Département Hématologie, CHU de Lyon-Sud, Lyon-Sud, France; 7Tennessee
Oncology, Nashville, TN, USA; 8Calvary Mater Newcastle Hospital, Waratah, NSW, Australia;
9Hematology Unit, Santa Maria delle Croci Hospital, Ravenna, Italy; 10Medical University ofŁódź, Copernicus Memorial Hospital, Łódź, Poland; 11Dana-Farber Cancer Institute, Boston,MA, USA; 12Alfred Hospital and Monash University, Melbourne, VIC, Australia; 14BeiGene
USA, Inc, San Mateo, CA, USA; 15Mari Sklodowska-Curie National Research Institute ofOncology, Kraków, Poland; 16IRCCS Ospedale San Raffaele, Milan, Italy; 17Università VitaSalute San Raffaele, Milan, Italy
Background: Zanubrutinib (zanu) is a next-generation, selective BTK inhibitor designed tohave high BTK specificity and minimize off-target effects. In several recent studies, fixedduration BCL2/BTK inhibitor combination treatment was tolerable and led to durable
responses in patients with CLL/SLL. As monotherapies, zanu and venetoclax (ven), the firstgeneration BCL2 inhibitor, have achieved high ORRs in patients with del(17p) and/or TP53mutation.
Aims: Here, preliminary results in patients with del(17p) and/or TP53 mutation who received
zanu + ven combination treatment in the SEQUOIA trial (arm D) are presented.
Methods: SEQUOIA (NCT03336333) is an open-label, global, phase 3 study; arm D is anonrandomized cohort of patients aged ≥65 years old (or 18-64 years old comorbidities) who
had TN CLL/SLL with del(17p) and/or TP53 mutation and met iwCLL criteria for treatment.
Patients received zanu (160 mg twice daily) lead-in for 3 cycles, then zanu + ven (ramp-up to400 mg once daily) for 24 cycles, followed by zanu monotherapy until progressive disease,
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unacceptable toxicity, or meeting early dose-stopping rules for either zanu or ven(simultaneous achievement of CR/CR with incomplete hematopoietic recovery [CRi] andundetectable minimal residual disease [uMRD; <1×10−4 by flow cytometry in peripheral blood(PB) and bone marrow (BM) on 2 consecutive tests ≥12 weeks apart]). Responses wereinvestigator assessed per modified iwCLL and Lugano criteria (SLL) with PB MRD
assessments every 3 cycles for 2 years and then every 6 cycles. Safety per CTCAE and riskof tumor lysis syndrome (TLS) per Cairo Bishop criteria pre-treatment and prior to ven
administration, were also assessed. Patients at high risk for TLS were those with any lymph
node ≥10 cm or ≥5 cm with absolute lymphocyte count ≥25×109/L.
Results: Between Nov 2019 and Jun 2022, 66 patients with centrally assessed del(17p)
and/or TP53 mutation were enrolled. Three discontinued treatment during the zanu lead-inperiod. As of Oct 31, 2023, with a median study follow-up of 28.6 months (range 0.4-47.4), 55
of 63 (87%) patients who initiated zanu + ven remained on treatment (16 on zanu + ven; 39
on zanu monotherapy after completing ven treatment). Among 66 treated patients, 52% weremale and the median age was 66 years (range, 26-87). Six patients discontinued the study (4deaths; 1 withdrawal; 1 lost to follow-up). In 65 response-evaluable patients, the ORR was
100% and the CR+CRi rate was 45% (Table). uMRD was achieved by 48% of patients in ≥1
PB sample. Median PFS was not reached and the 36-month estimated PFS was 92% (95%CI, 81%-97%). Ninety-seven percent of patients experienced ≥1 TEAE. The most common
all-grade non-hematologic TEAEs were COVID-19 (55%), diarrhea (41%), contusion (29%),
and nausea (29%). Grade ≥3 non-hematologic TEAEs occurred in 44% of patients; the mostcommon were diarrhea (8%) and hypertension (8%). The most common all grade and grade≥3 hematologic toxicity was neutropenia (21% and 17%, respectively). The proportion ofpatients at high risk for TLS decreased from 35% at screening to 3% after 3 cycles of lead-in
zanu and no TLS was reported.
Summary/Conclusion: Preliminary data demonstrate promising efficacy and tolerability ofzanu + ven combination treatment in patients with high-risk TN CLL/SLL with del(17p) and/or
TP53 mutation. The safety profile of zanu + ven was consistent with results of prior zanu
studies, and no new safety signals were identified.

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Table. Efficacy Outcomes in Patients With del(17p) and/or TP53 Mutationdel(17p)+ or TP53+(n=66)
65 (98)

Response evaluable, n (%)aBest overall response, n (%)
CR+CRi29 (45)
Nodular PR0PR
35 (54)
PR with lymphocytosis
1 (2)SD0ORR, n (%)
65 (100)
Best uMRD rate at any time in PB, n (%)
32 (48)aPatients who received ≥1 dose of zanu with ≥1 post-baseline disease assessment.

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