Single-Agent Ibrutinib Versus Real-World (RW) Treatments for Patients with Previously Untreated Chronic Lymphocytic Leukemia (CLL): Adjusted Comparison of Resonate-2™ with the Cllear and Lyon-Sud Rw Databases
Authors: Doubek Michael , Smolej Mudr. Lukas , Šimkovič Martin , Panovska Anna , Urbanova Renata , Lysak Daniel , Callet-Bauchu Evelyne , Bachy Emmanuel , Baseggio Lucile , Ferrant Emmanuelle , Diels Joris , Cabrieto Jedelyn , Nielsen Lasse , Salles Gilles 
Published: November 2021

Abstract
Introduction
Ibrutinib, a once-daily oral Bruton's tyrosine kinase inhibitor, has shown progression-free survival (PFS) or overall-survival (OS) benefit over chemoimmunotherapy (CIT) in multiple phase 3 studies in previously untreated patients with CLL, and significantly longer time to next treatment compared with CIT in previously untreated high-risk patients in a RW setting. We conducted an adjusted comparison of ibrutinib versus RW treatment for previously untreated CLL using patient-level data from the phase 3 RESONATE-2™ (NCT01722487) trial and RW databases from 2 countries.
Methods
Previously untreated patients with CLL, fulfilling RESONATE-2™ eligibility criteria (age ≥ 65, no del17p) were selected from 2 RW data sources containing electronic medical records for patients with CLL: Centre Hospitalier Lyon-Sud, France; CLLEAR CLL registry from 7 academic centers in the Czech Republic. PFS and OS were compared between patients from the ibrutinib arm of RESONATE-2™ with a median follow-up of 60 months, and those receiving physicians' choice (PC) treatment other than ibrutinib from the RW database, adjusting for differences in baseline characteristics including age, gender, del11q, IGHV status, RAI/BINET disease stage, and Eastern Cooperative Oncology Group (ECOG) score. Hazard ratios (HRs) for ibrutinib versus RW PC treatment were estimated using a multivariable Cox proportional hazards model including available baseline characteristics as covariates, and using an inverse probability weighted (IPW) Cox model with average treatment effect for treatment (ATT) weights derived from propensity scores estimated from a logistic regression including the same covariates.
Results
The analysis included 136 patients from the RESONATE-2™ study receiving ibrutinib and 920 previously untreated RW patients receiving PC treatment (Lyon-Sud n = 162, CLLEAR n = 758). Baseline characteristics were generally balanced between treatment groups. The most common PC regimens contained CIT and were fludarabine + cyclophosphamide + rituximab (FCR) (n = 227), bendamustine + rituximab (BR) (n = 201), and rituximab + chlorambucil (R + Chlor) (n = 116). Older age, male gender, del11q and advanced disease stage were independent risk factors for PFS and OS. When comparing ibrutinib versus the overall PC cohort, the adjusted HR (95% confidence interval [CI]) was 0.24 (0.16-0.34) for PFS and 0.33 (0.21-0.52) for OS (both p &lt; 0.0001). IPW-based comparative estimates were highly consistent for both PFS (HR = 0.27 [0.18-0.39]) and OS (HR = 0.39 [0.24-0.62]). ATT-weighted survival curves estimating PFS and OS for the RESONATE-2™ population as if treated with PC, showed a median value of 32.1 months and 72.5 months, respectively, while median values for Ibrutinib were not reached. When comparing ibrutinib versus FCR, BR, and R + Chlor, the adjusted HRs (95% CI) were 0.26 (0.17-0.38), 0.27 (0.18-0.41), and 0.27 (0.17-0.42), respectively, for PFS and 0.34 (0.20-0.56), 0.28 (0.16-0.49), and 0.61 (0.32-1.13), respectively, for OS (Figure).
Concl usions
Adjusted comparisons of the RESONATE-2™ trial and RW patient-level data demonstrates significantly improved PFS and OS for ibrutinib versus physician's choice treatment (predominantly CIT) in previously untreated patients with CLL. PFS and OS benefit for ibrutinib was consistent across a range of common regimens: FCR, BR, and R + Chlor. These results are consistent with data from phase 3 studies and support the use of ibrutinib for first-line CLL treatment.
Funding Source:
Sponsored by Janssen Pharmaceutica NV, and Pharmacyclics LLC, an AbbVie Company. The RW databases are independently owned. Writing assistance was provided by Emma Fulkes and Liqing Xiao of Parexel and funded by Janssen Pharmaceutica NV.
Figure 1 Figure 1.

Disclosures
Doubek: Janssen-Cilag, AbbVie, AstraZeneca, Amgen, Gilead, Novartis: Honoraria, Research Funding. Smolej: AbbVie, AstraZeneca, Gilead, Janssen-Cilag, and Roche: Consultancy, Honoraria, Other: Travel Grants. Šimkovič: AbbVie, AstraZeneca, Janssen-Cilag, Gilead, Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants. Lysak: Novartis, Janssen-Cilag, AbbVie; AstraZeneca: Honoraria, Research Funding. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Ferrant: AbbVie: Honoraria, Other: Travel, Accommodations, Expenses; AstraZeneca: Honoraria; Janssen: Other: Travel, Accommodations, Expenses. Diels: Janssen: Current Employment. Cabrieto: Janssen: Current Employment. Nielsen: Janssen: Current Employment. Salles: Allogene: Consultancy; Regeneron: Consultancy, Honoraria; Velosbio: Consultancy; Takeda: Consultancy; Rapt: Consultancy; Genentech/Roche: Consultancy; Epizyme: Consultancy, Honoraria; Debiopharm: Consultancy; Genmab: Consultancy; Incyte: Consultancy; Ipsen: Consultancy; Janssen: Consultancy; Kite/Gilead: Consultancy; Loxo: Consultancy; Miltneiy: Consultancy; Morphosys: Consultancy, Honoraria; Novartis: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria.