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3031 Long-term Clinical Outcomes in Patients with Waldenström Macroglobulinemia (WM) Who Received Zanubrutinib in the Phase 3 ASPEN Study: A Report from the Zanubrutinib Extension Study

Program: Oral and Poster Abstracts
Session: 623. Mantle Cell, Follicular, Waldenstrom’s, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Poster II
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Shirley D’Sa, MD1*, Meletios A. Dimopoulos, MD2, Wojciech Jurczak, MD, PhD3, Paula Marlton4*, Stephen P. Mulligan, MBBS, PhD, FRACP, FRCPA5, Bjorn E Wahlin, MD, PhD6, Magdalena Sobieraj-Teague7*, Andrew W. Roberts, MBBS, PhD8, Constantine S. Tam, MD, MBBS9, Jorge J. Castillo, MD10, Heather Allewelt, MD11*, Radha Prathikanti, MPH, MBA11*, Wai Y Chan11*, Tian Tian, PhD11*, Jingjing Schneider11*, Remus Vezan, MD, PhD11* and Stephen S. Opat, MBBS, FRACP, FRCPA12

1Centre for Waldenström’s Macroglobulinemia and Associated Disorders, University College London Hospital Foundation Trust, London, United Kingdom
2General Hospital of Athens-Alexandra, Llisia, Greece
3Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Malopolskie, Poland
4Princess Alexandra Hospital and University of Queensland, Brisbane, QLD, Australia
5Royal North Shore Hospital, Sydney, NSW, Australia
6Karolinska Universitetssjukhuset Solna, Solna, Sweden
7Flinders Medical Centre, Bedford Park, SA, Australia
8The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
9Alfred Hospital and Monash University, Melbourne, VIC, Australia
10Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
11BeiGene USA, Inc, San Mateo, CA
12Lymphoma Research Group, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia

Introduction: BTK inhibitors (BTKi) have become a standard of care for WM. The ASPEN study (BGB-3111-302; NCT03053440) directly compared outcomes of treatment with zanubrutinib and ibrutinib in patients with MYD88-mutated WM in cohort 1; patients with MYD88-wild type WM received zanubrutinib in cohort 2. At end of study, eligible patients could enroll in a long-term extension study, BGB-3111-LTE1 (LTE1, NCT04170283). Here, we report long-term outcomes in patients who received zanubrutinib in the ASPEN study, with extended follow-up from LTE1.

Methods: Patients who received zanubrutinib in the ASPEN study (cohort 1, Arm A and cohort 2) were included in this ad hoc analysis. Upon enrollment in LTE1, safety assessments were required every 3 mo and disease response assessments per investigator were required at least every 6 mo, using modified IWWM-6 response criteria (Owen 2013). Alternatively, investigators could assess “no evidence of progressive disease.”

Results: Of 129 patients who received zanubrutinib in the ASPEN study (cohort 1, n=101; cohort 2, n=28), 75 enrolled in LTE1 between Nov 11, 2021 and June 7, 2022; 72 continued zanubrutinib treatment. At ASPEN entry, the median age was 67 y (range, 39-85), and 81.3% (61/75) had relapsed/refractory WM, with a median of 1 prior line of therapy (range, 1-8). At LTE1 entry, the median age was 71 y (range, 44-89) and the median time since zanubrutinib treatment initiation was 50.6 mo (range, 40.7-59.9).

As of April 17, 2024, for patients enrolled in LTE1 from ASPEN, the median treatment duration in LTE1 was 23.8 mo (range, 0.4-29.4) and overall (ASPEN + LTE1) was 73.6 mo (range, 49.2-84.2). During LTE1, grade ≥3 and serious treatment-emergent adverse events (TEAEs) occurred in 28% and 23% of patients, respectively. No patients experienced TEAEs leading to treatment discontinuation in LTE1. Three patients (4%) had TEAEs leading to dose reduction (COVID-19 [n=2], intestinal diverticulum), and 3 had TEAEs leading to death (cardiac failure, fall/subdural hematoma, colorectal cancer). No grade ≥3 or serious TEAEs by preferred term occurred in ≥5% of patients during LTE1, whereas grade ≥3 neutropenia (24.0%), hypertension (8.0%), thrombocytopenia (6.7%), anemia (5.3%), back pain (5.3%) occurred in ≥5% of this subgroup during ASPEN. Of 42 patients with neutropenia/neutrophil count decreased, 17 (40.5%) received granulocyte-colony stimulating factor.

For all patients treated with zanubrutinib during ASPEN (n=129), the median follow-up was 69.8 mo (range, 1.6, 85.4) and median zanubrutinib treatment duration was 63.3 mo (range, 0.8, 84.2). Except for second malignancies (skin and non-skin cancer, each 6.0% at >5 y), the prevalence of TEAEs of interest for BTKis, including neutropenia, decreased over time. Specifically, at >1-2, >2-3, >3-4, >4-5 and >5 y, the prevalence of atrial fibrillation/flutter was 2.7%, 5.2%, 3.5%, 1.4%, and 1.5%, and of hypertension was 10.7%, 8.3%, 9.4%, 6.8%, and 6.0%, respectively.

For patients from cohort 1 (n=101, MYD88-mutated), the overall response rate (ORR, ≥minor response) was 96.1% and the rate of ≥very good partial response (VGPR+) was 40.2% versus 95.1% and 36.3%, respectively, at ASPEN final analysis. For patients from cohort 2 (n=26, confirmed MYD88-wild type), the ORR was 84.6% and the VGPR+ rate was 30.8% versus 80.8% and 30.8%, respectively, at ASPEN final analysis (Dimopoulos et al. JCO. 2023). Median duration of response was 55.7 mo (95% CI, 31.3, 68.4) for cohort 1 and 41.1 mo (95% CI, 15.7, NE) for cohort 2. In cohort 1, the 60-mo event-free rates for progression-free survival (PFS) were 74.8% (95% CI, 64.5, 82.5) overall; 70% (95% CI, 50.1, 83.2) for patients with CXCR4WHIM (n=33; 4 unknown); and 57.3% (95% CI, 35, 74.4) for patients with TP53mut (n=26; 4 unknown). In cohort 2, the 60-mo event-free rate for PFS was 39.3% (95% CI, 20, 58.1); 1 patient in cohort 2 had CXCR4WHIM (6 unknown) and 4 had TP53mut (6 unknown). The 60-mo event-free rates for overall survival were 82.8% (95% CI, 73.5, 89.1) for cohort 1 and 79.9% (95% CI, 56.4, 90.8) for cohort 2. As of April 17, 2024, 69.3% (52/75) of patients with WM remained on zanubrutinib.

Conclusions: With a median follow-up of 5.8 y, responses in patients with WM treated with zanubrutinib in ASPEN remained durable; furthermore, the tolerability and safety profile of zanubrutinib remained favorable, with most TEAEs of interest for BTKis decreasing in prevalence with ongoing treatment.

Disclosures: D’Sa: Sanius Health: Consultancy; BeiGene: Consultancy, Honoraria, Other: Travel, accommodations, expenses, Research Funding, Speakers Bureau; Cellectar: Honoraria. Dimopoulos: Swixx: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jurczak: Regeneron: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Janssen Cilag: Consultancy, Research Funding; Lilly: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Merck: Research Funding; MSD: Research Funding. Marlton: Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas; Janssen; BeiGene; AstraZeneca; Otsuka; AbbVie; Menarini; Pfizer; MSD; Jazz; Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie, BeiGene: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mulligan: AbbVie: Speakers Bureau; BeiGene: Speakers Bureau; Janssen: Speakers Bureau. Wahlin: Morphosys: Honoraria; Gopal: Research Funding; Gilead Sciences: Research Funding; Roche: Consultancy, Honoraria; Incyte: Honoraria. Roberts: AbbVie: Patents & Royalties: Patent assigned to AbbVie, Research Funding. Tam: Lilly: Honoraria; Gilead: Honoraria; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding. Castillo: Kite Pharmaceuticals: Consultancy; Mustang Bio: Consultancy; Cellectar Biosciences: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Janssen: Consultancy; BeiGene: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Allewelt: St. Jude Children’s Research Hospital: Patents & Royalties; Nkarta: Current Employment, Current equity holder in publicly-traded company, Other: Travel support; BeiGene: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Prathikanti: BeiGene: Current Employment. Chan: BMS: Current equity holder in publicly-traded company; BeiGene: Current Employment, Current equity holder in publicly-traded company. Tian: BeiGene: Current Employment. Schneider: BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: Travel, accommodations, expenses. Vezan: BeiGene: Current Employment. Opat: Pharmacyclics: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

*signifies non-member of ASH