title: Indirect Treatment Comparisons of Ibrutinib Versus Physician's Choice and Idelalisib Plus Ofatumumab in Patients With Previously Treated Chronic Lymphocytic Leukemia.
abstract: Treatment options for patients with relapsed or refractory chronic lymphocytic leukemia (R/R CLL) are limited. Until recently, few effective treatment options existed, and even with the advent of new agents, studies evaluating comparative efficacy are scarce. In the Ibrutinib Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia (RESONATE) Phase III study, ibrutinib, an oral, once-a-day, first-in-class covalent Bruton tyrosine kinase inhibitor, improved progression-free survival (PFS) and overall survival (OS) compared with ofatumumab (PFS hazard ratio [HR] = 0.106 and OS HR = 0.369 [adjusted for crossover] at a median of 16 months' follow-up). We sought to establish the relative efficacy of ibrutinib versus other treatment options for patients with R/R CLL using indirect comparison methods.
  
  
  
  A systematic literature review was conducted to identify clinical trials sharing a common treatment arm with the RESONATE Phase III trial such that a network meta-analysis or indirect treatment comparisons (ITCs) could be conducted. Two trials were identified, each using the same comparator (ofatumumab) as the RESONATE study. Two pairwise ITCs were conducted using the Bucher method to establish the relative treatment efficacy of ibrutinib versus (1) idelalisib plus ofatumumab in the first study and (2) physician's choice, defined as a mix of therapies commonly used in R/R CLL, in the second study. Odds ratios for these ITCs were calculated for overall response rate (ORR) and HRs for PFS and OS.
  
  
  
  A strong and consistent trend of superiority for ibrutinib was observed via these ITC models with idelalisib plus ofatumumab and physician's choice for ORR, PFS, and OS. Ibrutinib revealed prolonged PFS and OS versus comparators (PFS HR = 0.06; 95% CI, 0.04-0.11; and OS HR = 0.25; 95% CI, 0.12-0.54), physician's choice (PFS HR = 0.41; 95% CI, 0.25-0.66; and OS HR = 0.50; 95% CI, 0.23-1.08), and idelalisib plus ofatumumab. These findings were robust and continued to favor ibrutinib when adjusting (where appropriate) for underlying differences in patient population between the trials. Some trial differences were not accounted for in the models and thus some limitations remain; however, consistency of results supports the overall findings.
  
  
  
  In a randomized Phase III study, ibrutinib significantly improved ORR, PFS, and OS in patients with R/R CLL versus ofatumumab. In ITC models that used ofatumumab as the common comparator, ibrutinib appears to have higher ORR and longer PFS and OS versus both idelalisib plus ofatumumab and physician's choice. In the absence of head-to-head studies and taking into consideration inherent limitations of ITCs, these models provide useful estimates of comparative efficacy.
authors.affiliation: Modeling and Simulation, Evidera, Bethesda, Maryland. Electronic address: Sonja.sorensen@evidera.com.
authors.forename: Sonja
authors.initials: S
authors.lastname: Sorensen
authors.affiliation: Janssen Research & Development, Raritan, New Jersey.
authors.forename: Mark
authors.initials: M
authors.lastname: Wildgust
authors.affiliation: Janssen Global Services, Raritan, New Jersey.
authors.forename: Nishan
authors.initials: N
authors.lastname: Sengupta
authors.affiliation: Janssen Global Market Access & Policy-Oncology, Toronto, Ontario, Canada.
authors.forename: Cristina
authors.initials: C
authors.lastname: Trambitas
authors.affiliation: Janssen Health Economics & Market Access EMEA Statistics & Modelling, Beerse, Belgium.
authors.forename: Joris
authors.initials: J
authors.lastname: Diels
authors.affiliation: Janssen Health Economics & Market Access EMEA Statistics & Modelling, Beerse, Belgium.
authors.forename: Suzy
authors.initials: S
authors.lastname: van Sanden
authors.affiliation: Meta Research, Evidera, Waltham, Massachusetts.
authors.forename: Yingxin
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Modeling and Simulation, Evidera, Bethesda, Maryland.
authors.forename: Emily
authors.initials: E
authors.lastname: Dorman
mesh_terms: D006801:Humans; D000225:Adenine / Q000031:analogs & derivatives; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D018572:Disease-Free Survival; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011687:Purines / Q000008:administration & dosage; D011720:Pyrazoles / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D052999:Quinazolinones / Q000008:administration & dosage; D016032:Randomized Controlled Trials as Topic; D012008:Recurrence; D016896:Treatment Outcome
chemical_list: D000225:Adenine; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C551803:ibrutinib; C552946:idelalisib; C527517:ofatumumab; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D052999:Quinazolinones
keywords: chronic lymphocytic leukemia; ibrutinib; idelalisib; indirect treatment comparison; ofatumumab