IMPROVED EFFICACY AND SAFETY OF ZANUBRUTINIB VERSUS IBRUTINIB IN PATIENTS WITH RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA (R/R CLL) IN CHINA: A SUBGROUP OF ALPINE

Abstract

Introduction: Zanubrutinib is an irreversible, potent, next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target inhibition. In a randomized phase 3 study (ALPINE; NCT03734016), zanubrutinib was compared head to head with ibrutinib as a treatment for R/R CLL (including small lymphocytic lymphoma [SLL]). In the predefined progression-free survival (PFS) final analysis, zanubrutinib demonstrated superior efficacy and a favorable safety profile versus ibrutinib (Brown et al. NEJM 2022). Data from the prespecified subgroup in pts from China are reported here. Methods: Patients (pts) with R/R CLL/SLL who had received ≥1 prior line of therapy and had measurable disease by imaging were randomized (1:1) to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily, until disease progression or unacceptable toxicity. Randomization included stratification by geographical region (China vs. non-China). Data from the subgroup in pts from China were descriptively analyzed. Results: A total of 90 pts in China with R/R CLL/SLL (zanubrutinib, n = 47; ibrutinib, n = 43) were enrolled. Disease characteristics and baseline demographics were balanced between zanubrutinib and ibrutinib (aged ≥65 y [40% vs. 37%]; unmutated IGHV [59.6% vs. 62.8%]; del17p/TP53 mutated [34.0% vs. 32.6%]) with a median age of 60 and 61 y, respectively. Median number of prior therapies was 1. At a median follow-up of 25.3 mo, PFS by independent review committee (IRC) was improved with zanubrutinib versus ibrutinib (hazard ratio [HR]: 0.24; 95% CI 0.09-0.64; nominal 2-sided P = 0.002) with 18-mo landmark PFS rates of 88.9% versus 71.6% for zanubrutinib and ibrutinib, respectively (Figure). Additionally, zanubrutinib was more favorable in high-risk del17p/TP53 mutation (18-mo landmark 80.0% vs. 64.3%; HR: 0.51; 95% CI 0.12-2.13). ORR also favored zanubrutinib over ibrutinib (87.2% vs. 76.7%; 95% CI 0.93-1.38) by IRC. The treatment discontinuation rate was lower with zanubrutinib (14.9%) versus ibrutinib (41.9%) with most due to progressive disease (6.4% vs. 20.9%) and adverse events (AEs; 6.4% vs. 14.0%). Rates of grade ≥3 AEs (64.4% vs. 72.1%) and serious AEs (35.6% vs. 51.2%) were lower with zanubrutinib versus ibrutinib. With zanubrutinib, 4 deaths (8.5%) were reported compared to 8 deaths (18.6%) with ibrutinib (HR: 0.45; 95% CI 0.14–1.50). Keywords: Chronic Lymphocytic Leukemia (CLL), Molecular Targeted Therapies Conflicts of interests pertinent to the abstract L. Fu Employment or leadership position: BeiGene Stock ownership: BeiGene T. Salmi Employment or leadership position: BeiGene Stock ownership: BeiGene K. Wu Employment or leadership position: BeiGene Stock ownership: BeiGene L. Wang Employment or leadership position: BeiGene Stock ownership: BeiGene J. R. Brown Consultant or advisory role AbbVie, Acerta/AstraZeneca, BeiGene, Genentech/Roche, Grifols Worldwide Operations, Hutchmed, iOnctura, Janssen, Kite, Loxo/Lilly, MEI Pharma, Numab Therapeutics, Pfizer, Pharmacyclics Research funding: BeiGene, Gilead, iOnctura, Loxo/Lilly, MEI Pharma, TG Therapeutics