Introduction: ALPINE, a randomized, multinational phase 3 study (NCT03734016) in patients with R/R CLL/SLL, established the statistical and clinically meaningful superiority of zanubrutinib over ibrutinib on progression-free survival (PFS) and overall response rate (ORR) and confirmed the favorable safety/tolerability profile of zanubrutinib (Brown et al. NEJM; 2022). Now, with 3 years of overall study follow-up, we report the results of an extended follow-up analysis.

Methods: As previously published, patients with R/R CLL/SLL who had received ≥1 prior therapy and had measurable disease were randomized 1:1 to receive zanubrutinib or ibrutinib. Efficacy assessments, including PFS and ORR, were evaluated by the investigator based on 2008 iwCLL criteria; sensitivity analyses to confirm PFS results were also conducted. Updated safety analyses were performed. All reported P-values are descriptive.

Results:Overall, 652 patients were randomized to receive zanubrutinib (n=327) or ibrutinib (n=325). As of 15 May 2023, 63.3% (n=207/327) of patients remain on zanubrutinib and 52.3% (n=170/325) remain on ibrutinib. At a median study follow-up of 36.3 months, benefit of zanubrutinib over ibrutinib was sustained (HR: 0.67 [95% CI, 0.52-0.86]; 2-sided P=.002; Fig 1). At 36 months, the PFS rates were 65.8% with zanubrutinib and 54.3% with ibrutinib. Benefits in PFS with zanubrutinib were also observed across major subgroups, including in patients with del(17p)/ TP53 mutations (HR: 0.52 [95% CI, 0.32-0.83] 2-sided P=.005) where 36-month PFS rates were 60.1% and 43.6%, respectively. Additionally, the zanubrutinib PFS benefit was confirmed in a sensitivity analysis that included only progression and death events that occurred on active treatment (HR: 0.69 [95% CI, 0.49-0.97]; 2-sided P=.031). ORR remained higher with zanubrutinib compared with ibrutinib (85.0% vs 74.8%; 2-sided P=.001). Responses deepened in both arms with CR/CRi rates of 10.1% (zanubrutinib) and 7.4% (ibrutinib); therate of PR-L or better was 90.2% vs 82.8%, respectively. Fifty-nine (18.0%) patients treated with zanubrutinib and 71 (21.8%) treated with ibrutinib had died (OS HR: 0.76 [95% CI, 0.54-1.08]); 36-month OS rates were 82.6% (zanubrutinib) and 79.7% (ibrutinib).

In this extended follow-up, median treatment duration was 34.7 months (zanubrutinib) and 31.5 months (ibrutinib). Across both arms, the most common reasons for treatment discontinuation were AEs (20.2%, zanubrutinib; 24.9%, ibrutinib) and progressive disease (12.2%, zanubrutinib; 16.3%, ibrutinib). Dose interruption and dose reduction due to AEs were 59.6% vs 61.1% and 14.2% vs 17.6% with zanubrutinib vs ibrutinib, respectively.

The most common AEs of any grade with zanubrutinib and ibrutinib were COVID-19 (37.3% vs 25.6%), diarrhea (17.9% vs 25.6%), and upper respiratory tract infection (25.9% vs 17.3%). Rates of any grade ≥3 AEs and serious AEs were 72.2% vs 75.6% and 49.7% vs 57.4% with zanubrutinib vs ibrutinib, respectively. Most commonly reported grade ≥3 AEs were neutropenia (17.3% vs 16.4%) and hypertension (15.1% vs 12.0%). Rates of serious infections were 30.6% in each treatment arm. Discontinuation rates due to cardiac disorders were lower with zanubrutinib (0.6% [n=2]) vs ibrutinib (4.6% [n=15]). Overall cardiac events remain lower with zanubrutinib, including atrial fibrillation/flutter (6.2% vs 16.0%; 2-sided P<.0001). Across this study, no grade 5 AEs due to cardiac disorders were observed with zanubrutinib but were reported in 6 patients (1.9%) with ibrutinib ( Table 1).

Conclusions: ALPINE was the first study to demonstrate PFS superiority in a head-to-head comparison of BTK inhibitors. At a median follow-up of 3 years, the study showed sustained PFS benefits of zanubrutinib over ibrutinib. The durable PFS benefits with zanubrutinib were observed across major subgroups, including multiple sensitivity analyses. The overall safety/tolerability profiles were consistent with previous reports for both treatments. The cardiac safety profile remained favorable for zanubrutinib compared with ibrutinib, with no new safety signals emerging with longer follow-up. With over 3 years of treatment, zanubrutinib continues to be a more efficacious and better tolerated treatment than ibrutinib for patients with R/R CLL/SLL. At time of presentation, data with further follow-up will be presented.

Brown:Loxo/Lilly: Consultancy, Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Consultancy; Numab Therapeutics: Consultancy; Merck: Consultancy; Gilead: Research Funding; Grifols Worldwide Operations: Consultancy; Kite: Consultancy; BeiGene: Consultancy, Research Funding; iOnctura: Consultancy, Research Funding; SecuraBio: Research Funding; Alloplex Biotherapeutics: Consultancy; Hutchmed: Consultancy; MEI Pharma: Research Funding; Pfizer: Consultancy; Genentech/Roche: Consultancy; Abbvie: Consultancy; Acerta/AstraZeneca: Consultancy. Eichhorst:Janssen: Consultancy, Research Funding, Speakers Bureau; Lilly: Consultancy, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding, Speakers Bureau; BeiGene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau. Lamanna:Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy; Octapharma: Research Funding; Eli Lilly/Loxo: Research Funding; Genentech: Consultancy, Research Funding; Janssen: Consultancy; AstraZeneca: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; TG Therapeutics: Research Funding; Oncternal: Research Funding; MingSight: Research Funding; BeiGene: Consultancy, Research Funding. O'Brien:Johnson & Johnson: Consultancy; Janssen: Consultancy; Lilly: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Astrazeneca: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding; Regeneron: Research Funding; Pharmacyclics: Consultancy, Research Funding. Tam:AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; LOXO: Honoraria; Novartis: Honoraria; Roche: Honoraria. Qiu:Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences: Current Employment; BeiGene, Janssen, Roche, AstraZeneca, Takeda: Speakers Bureau. Jurczak:AstraZeneca: Consultancy; AbbVie: Consultancy; BeiGene: Consultancy; Eli Lilly: Consultancy; Pfizer: Consultancy; Roche: Consultancy; SOBI: Consultancy; Takeda: Consultancy; AbbVie: Research Funding; AstraZeneca: Research Funding; Bayer: Research Funding; BeiGene: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Eli Lilly: Research Funding; Merck: Research Funding; Pfizer: Research Funding; Roche: Research Funding; SOBI: Research Funding; Takeda: Research Funding. Simkovic:4th Department of Internal Medicine-Haematology, Faculty of Medicine in Hradec Kralove, University Hospital and Charles University in Prague, Hradec Kralove, Czech Republic: Current Employment; AbbVie, AstraZeneca, Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie, AstraZeneca, J&J, Beigene, Gilead, Baxter, Novartis, Abbot, Sanofi, Merck, GSK, Sanofi, Vertex, Eli Lilly, Genmab: Current equity holder in publicly-traded company. Mayer:BeiGene: Research Funding. Ferrajoli:Beigene: Research Funding; GenMab: Research Funding; Genetech: Honoraria; AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Janssen: Honoraria. Weinkove:Fisher & Paykel Healthcare: Current equity holder in publicly-traded company; BioOra: Research Funding; BeiGene: Honoraria; Janssen: Honoraria, Research Funding; AbbVie: Honoraria. Robak:BeiGene: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Regeneron: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; OctoPharma: Honoraria, Research Funding; Abbvie: Honoraria. Yimer:Abbvie, Amgen, AstraZeneca, BeiGene USA, Inc., GlaxoSmithKline, Janssen Biotech, Karyopharm Therapeutics, Takeda: Speakers Bureau. Wang:BeiGene: Current Employment, Current equity holder in publicly-traded company. Salmi:BeiGene: Current Employment, Current equity holder in publicly-traded company. Wang:BeiGene Inc.: Current Employment. Li:BeiGene: Current Employment, Current equity holder in publicly-traded company. Wu:BeiGene: Current Employment, Current equity holder in publicly-traded company. Cohen:BeiGene: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Shadman:BeiGene: Consultancy, Research Funding; Mustang Bio: Consultancy, Research Funding; ADC therapeutics: Consultancy; Vincerx: Research Funding; Eli Lilly: Consultancy; Genmab: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; MorphoSys/Incyte: Consultancy, Research Funding; MEI Pharma: Consultancy; Fate Therapeutics: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy, Research Funding; Regeneron: Consultancy; TG Therapeutics: Research Funding.

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