A MATCHING‐ADJUSTED INDIRECT COMPARISON OF THE EFFICACY AND SAFETY OF ACALABRUTINIB VERSUS ZANUBRUTINIB IN RELAPSED OR REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA

Abstract

Introduction: Next-generation Bruton tyrosine kinase inhibitors (BTKis) acalabrutinib (acala) and zanubrutinib (zanu) were compared with the standard of care BTKi ibrutinib in relapsed/refractory chronic lymphocytic leukemia (RR CLL) in the head-to-head randomized clinical trials (RCTs) ELEVATE-RR and ALPINE, respectively. However, differences in these RCT’s populations prevent comparison of acala and zanu. ASCEND, another RCT assessing acala, had a similar population to ALPINE but a different comparator. Thus, we used unanchored matching-adjusted indirect comparison (MAIC) to compare the efficacy and safety of acala vs zanu using individual patient data (IPD) from ASCEND and published aggregate data from ALPINE. Methods: Acala IPD from ASCEND were weighted to match zanu baseline data from ALPINE. This reduced differences in variables that were prognostic/effect-modifying of progression-free survival (PFS) in an exploratory multivariate cox regression analysis of ASCEND. These included sex, ECOG PS, bulky disease, prior chemoimmunotherapy, del(11q), del(17p), TP53 without del(17p), IGHV status, region, age, prior lines of therapy and Rai stage. An efficacy analysis assessed investigator-assessed PFS (INV PFS) in randomized patients with baseline data (acala, n = 149; zanu, n = 327). Pseudo IPD for INV PFS for zanu were obtained from Kaplan-Meier curves. A safety analysis assessed odds ratios (ORs) of adverse events (AEs) in treated patients with baseline data (acala, n = 148; zanu, n = 324). To compare the incidence of AEs, an artificial data cut-off (Feb 21, 2020) was imposed for acala to match the zanu median treatment exposure (both 28.4 months). Results: After matching, the effective sample size of acala was 99 (66.6%; 65% male; median age 66 years). 12- and 24-month INV PFS are shown in Table 1. The MAIC hazard ratio (HR) for INV PFS is similar for acala vs zanu: HR 0.90, 95% confidence interval (CI) 0.60–1.36. The risk of having grade ≥3 AE (OR 0.66, 95% CI 0.41–1.05), atrial fibrillation (AF; OR 1.32, 95% CI 0.56–3.08), grade ≥3 AF/atrial flutter (OR 0.60, 95% CI 0.12–2.89), grade ≥3 hemorrhage (OR 0.61, 95% CI 0.19–2.03) or an AE leading to discontinuation (OR 1.14, 95% CI 0.61–2.13) was similar with acala vs zanu. The risk of having a serious AE (OR 0.61, 95% CI 0.39–0.97), hypertension (any grade: OR 0.18, 95% CI 0.09–0.37; grade ≥3: OR 0.22, 95% CI 0.09–0.54), any grade hemorrhage (OR 0.54, 95% CI 0.34–0.87) or an AE leading to dose reduction (OR 0.30, 95% CI 0.14–0.67) favored acala vs zanu. Conclusions: Acala and zanu have a similar efficacy in RR CLL, while acala has a lower risk of grade ≥3 hemorrhage, any grade and grade ≥3 hypertension and dose reduction due to AEs vs zanu. Limitations of MAICs mean results should be viewed as hypothesis-generating. Encore Abstract—previously submitted to ASCO 2023, EHA 2023 The research was funded by: AstraZeneca Keyword: Chronic Lymphocytic Leukemia (CLL) Conflicts of interests pertinent to the abstract P. Ghia Consultant or advisory role AbbVie, AstraZeneca, BeiGene, BMS, Janssen, Lilly/Loxo Oncology, MSD, Roche Honoraria: AbbVie, AstraZeneca, BeiGene, BMS, Janssen, Lilly/Loxo Oncology, MSD, Roche Research funding: AbbVie, AstraZeneca, Janssen, Roche A. Skarbnik Consultant or advisory role AstraZeneca, Abbvie, Genentech, Genmab, Novartis, Kite Pharma, Epizyme, Janssen, Morphosys, Pharmacyclcics, SeaGen, TG Therapeutics, Lilly (LOXO) Other remuneration: Speakers' Bureau: AstraZeneca, Abbvie, Beigene, Celgene, Genentech, Janssen, Kite Pharma, Pharmacyclics, SeaGen, TG Therapeutics M. Miranda Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca A. S. Yong Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca J. Roos Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca Other remuneration: Patient/Royalties/Other Intellectual Property: CalciMedica R. Hettle Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca S. Palazuelos-Munoz Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca V. Shetty Employment or leadership position: AstraZeneca Stock ownership: Verona Pharma A. Kittai Consultant or advisory role Abbvie, AstraZeneca, Beigene, BMS, Eli Lilly, Janssen, KITE Research funding: AstraZeneca Other remuneration: Speaker's bureau: Beigene