Comparative Evaluation of Ibrutinib in Treatment of Chronic Lymphocytic Leukemia Using Simulation Modeling
Authors: Peng Siyang , Pan Feng , Sorensen Sonja , Dorman Emily , Xu Yingxin , Sallum Rachel , Gaudig Maren , Sengupta Nishan , Wildgust Mark , Sun Steve 
Published: October 2019

Abstract
Background
Treatment options for chronic lymphocytic leukemia (CLL) patients who received prior therapy are limited, especially for patients in high risk categories, such as del 17p; new therapies are urgently needed. In the Phase III RESONATE (Byrd, 2014), single agent ibrutinib, an oral, once-a-day, first-in-class covalent Bruton's tyrosine kinase inhibitor, was associated with improved progression-free survival (PFS, HR=0.215), overall survival (OS, HR=0.387) and overall response rate (ORR, 63% vs. 4%) compared with ofatumumab alone. Here we assessed the availability and comparability of clinical data for key therapies used in pre-treated CLL patients with ibrutinib and project long-term outcomes of ibrutinib for comparable studies using a simulation model.
Methods
A systematic literature review (SLR) identified relapsed or refractory CLL clinical trials on the following regimens: bendamustine ± rituximab (BR), fludarabine + cyclophosphamide + rituximab (FCR), ofatumumab, idelalisib + rituximab (IR), and rituximab. Patient populations and outcomes (ORR, PFS, and OS) were compared. A health state model was then developed to simulate long-term PFS and OS, comparing other therapies with ibrutinib. The model simulated treatment of a cohort of patients with pre-treated CLL until death or until disease progression, at which point they were simulated to receive subsequent treatment or best supportive care. Available Kaplan-Meier data were used to estimate longer-term projections of PFS and OS of comparable trials.
Results
The SLR identified few (n=36) relevant trials, only 4 of which were RCTs; comparison to ibrutinib through a common comparator was not possible. Pivotal trials was identified for each therapy based on the comparability to the RESONATE population, largest sample size and greatest amount of data reported. Selected trials (Table) showed significant heterogeneity between study populations, including variations in adverse cytogenetics (e.g. del 17p, del 11q), treatment line, and other characteristics (e.g. bulky disease) which have important ramifications on health outcomes. Three trials were excluded from simulation modeling: Robak (FCR) and LeBlond (BR) consisted of less heavily pre-treated patients than RESONATE; Furman et al. 2014 (rituximab and idelalisib+rituximab), enrolled a similar population to RESONATE aside from 17 p del, however, long-term safety and efficacy outcomes are limited due to the short follow-up in the idelalisib trial. Simulation over a 10 year horizon resulted in prolonged estimated mean OS for ibrutinib compared to ofatumumab (66 months versus 39 months). Despite the ibrutinib patients consisting of more heavily pre-treated, worse adverse cytogenetics and high risk features than those included in the BR and FCR studies, naïve comparison of long-term OS was projected to be 26 months and 8 months longer with ibrutinib respectively.
Conclusion
Comparisons of outcomes across trials are inherently limited by differences in populations, trial designs, and measurements. In this limited, naïve comparison of high risk CLL patients, ibrutinib is reasonably expected to provide incremental OS over BR and FCR in the pre-treated CLL setting, even when considering the RESONATE patient population included more heavily pre-treated patients and those with worse cytogenetics. The most rigorous comparison, using comparative data from a head-to-head trial, indicated that ibrutinib significantly prolonged PFS and OS compared to ofatumumab, which has established activity in hard-to-treat patients.
Table. Patient Characteristics Patient Characteristics RESONATE RESONATE Fischer Badoux Furman Furman Robak FCR LeBlond BR Ibrutinib Ofatumumab BR FCR Rituximab + placebo Rituximab + idelalisib Sample Size 195 196 78 284 110 110 276 58 Median age (range) 67(30- 88) 67 (37- 88) 66.5 (42-86) 60 (NA) 71 (47-92) 71 (48- 90) 63 (35-83) 75 (49-87) Del 17p, (%) 32.30% 32.70% 19.20% 7% 28.20% 23.60% 7% 12% Median # of prior therapies (range) 3 (1-12) 2 (1-13) 2 (1-5)* 2 (1-10) 3 (1-9) 3 (1-12) 1 (1-1) 1 (1-2) % ≥3 prior therapies 52.80% 45.90% 43% 31% NA NA 0% 0% % Purine analog refractory 44.60% 44.90% 28.2%~ 19%~ NA NA NA NA

Disclosures
Peng: Janssen: Consultancy; Evidera: Employment. Pan:Janssen: Consultancy; Evidera: Employment. Sorensen:Evidera: Employment; Janssen: Consultancy. Dorman:Janssen: Consultancy; Evidera: Employment. Xu:Janssen: Consultancy; Evidera: Employment. Sallum:Evidera: Employment; Janssen: Consultancy. Gaudig:Janssen: Employment. Sengupta:Janssen: Employment. Wildgust:Janssen Global Services: Employment. Sun:Janssen: Employment.