Ibrutinib (4) – Imbruvica®

• Clinical trials
  • The RESONATE-2 (PCYC-1115-CA) trial is an open-label, randomised, multicentre trial designed to investigate the efficacy and safety of ibrutinib compared with the comparator chlorambucil.
  • The CLL11 trial is a randomised, open-label, three-arm trial designed to investigate various chemotherapies and chemoimmunotherapies in patients aged 18 years and over with chronic lymphocytic leukaemia requiring treatment but who have not previously received treatment.
  • The COMPLEMENT-1 registration trial investigated the efficacy and safety of chlorambucil in combination with ofatumumab compared with chlorambucil monotherapy in patients aged 18 years and over with previously untreated CLL who were not eligible for chemoimmunotherapy with FCR.

a) Patients with previously untreated CLL who are eligible for FCR therapy

• For patients with untreated CLL who are eligible for FCR therapy, an additional benefit is not proven.
• The pharmaceutical manufacturer has not submitted any direct comparative studies against the appropriate comparator therapy to demonstrate the additional benefit of ibrutinib in patients with previously untreated CLL who are eligible for FCR therapy, fludarabine in combination with cyclophosphamide and rituximab.
• As the RESONATE-2 trial only included patients for whom FCR was explicitly unsuitable, this study cannot be used to assess additional benefit in the present population.

b) Patients with untreated CLL for whom FCR therapy is not an option

• For patients with untreated CLL for whom treatment with FCR is not an option, an additional benefit is not proven.
• Overall, not all criteria for an adequate indirect comparison are met. The studies considered differ with regard to relevant criteria, meaning that the evidence presented cannot be taken into account when determining the additional benefit of ibrutinib in patients with CLL for whom non-fludarabine-based chemoimmunotherapy is suitable.
• Patient characteristics
  • A significant proportion of patients younger than 65 years were included in the CLL11 and COMPLEMENT-1 studies, whereas the inclusion criteria for the RESONATE-2 study specified a minimum age of 65 years.
  • Approximately 20% of the patients studied in CLL11 and 31% of those in COMPLEMENT-1 were younger than 65 years.
  • The populations in the individual studies also differed in terms of comorbidities assessed using the CIRS score. Patients in the CLL11 and COMPLEMENT-1 studies had, on average, higher CIRS scores than those in the RESONATE-2 study.
• Dosage of chlorambucil
  • The dosage of the bridge comparator chlorambucil varied across the individual studies.
  • In the RESONATE-2 study, chlorambucil was administered on days 1 and 15 of each 28-day cycle, with the dose based on body weight (0.5 mg/kg body weight).
  • In the CLL11 study, however, the number of cycles was limited to 6. Furthermore, the initial dose of chlorambucil was not adjusted during the course of treatment based on tolerability.
  • In the COMPLEMENT-1 study, patients were treated – contrary to the product information – with a body-surface-area-based dose of chlorambucil that was very high compared with the other two studies (10 mg/m² body surface area on days 1 to 7 of each cycle).
• Suitability for FCR therapy
  • It is also unclear whether all study patients included in the assessment of this patient population were no longer eligible for FCR therapy.
  • In particular, the latter criterion – on the basis of which ineligibility was defined for the majority of patients – is, even according to current guidelines, not sufficient on its own to rule out FCR therapy.
  • For all three individual studies relevant to the assessment, it must therefore be assumed that an unspecified proportion of patients would still have been eligible for FCR therapy and consequently do not form part of the defined therapeutic indication.
• Conclusion
  • Overall, not all criteria for an adequate indirect comparison are met. The studies considered differ with regard to relevant criteria, meaning that the evidence presented cannot be taken into account to determine the additional benefit of ibrutinib in patients with CLL for whom a non-fludarabine-based chemoimmunotherapy is suitable.

c) Patients with untreated CLL for whom chemoimmunotherapy is not an option and who do not have a 17p deletion or TP53 mutation

• For patients with untreated CLL for whom chemoimmunotherapy is not an option and who do not have a 17p deletion or TP53 mutation, additional benefit is not proven.
• Overall, the evidence presented is not sufficient to demonstrate an additional benefit of ibrutinib in patients in sub-indication 2. It is unclear to what extent only patients for whom chemoimmunotherapy is not an option were included. Furthermore, the appropriate comparator therapy was not adequately implemented.
• The RESONATE-2 study is also unsuitable for demonstrating additional benefit in the patient population under consideration because chlorambucil does not constitute an appropriate implementation of best supportive care (BSC) for all patients considered here.
• The appropriate comparator therapy, BSC, is defined as the best possible, individually optimised supportive care aimed at alleviating symptoms and improving quality of life. The treatment with the cytostatic agent chlorambucil, which was mandatorily prescribed in the comparator arm of RESONATE-2, does not meet this definition.
• Conclusion
  • Overall, the evidence presented is not sufficient to demonstrate any additional benefit of ibrutinib in patients in sub-indication 2.

Courtesy translation only, please refer to the German original.