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

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 < 0.0001). IPW-based comparative estimates were highly consistent