Ibrutinib (8) – Imbruvica®

• Clinical trials
  • The ECOG-E1912 trial is an open-label, randomised, controlled trial comparing ibrutinib in combination with rituximab against immunochemotherapy comprising fludarabine + cyclophosphamide + rituximab.

a) Adult patients with previously untreated chronic lymphocytic leukaemia who are eligible for treatment with fludarabine in combination with cyclophosphamide and rituximab (FCR)

• There is a hint of considerable additional benefit for ibrutinib in combination with rituximab for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia who are eligible for treatment with FCR.
• Overall, based on the clear advantage in OS and the advantages in AEs, there is a hint of a considerable additional benefit for ibrutinib plus rituximab.
• mortality
  • A statistically significant difference in favour of ibrutinib in combination with rituximab was observed for overall survival compared with FCR immunochemotherapy (hazard ratio (HR): 0.06 [95% confidence interval (CI): 0.01; 0.48]; p-value < 0.001).
  • It should be noted that the interpretability of the event rates is limited due to the minor event rates observed to date.
  • However, given the magnitude of the effect, and even taking these limitations into account, the advantage in overall survival with ibrutinib plus rituximab is nevertheless regarded as a significant therapeutic improvement.
• morbidity
  • Progression-free survival (PFS) was the primary endpoint in the ECOG-E1912 study.
  • At the time of the second data cut-off, there was a statistically significant advantage in favour of ibrutinib plus rituximab (HR: 0.25 [95% CI: 0.14; 0.48]; p < 0.0001).
  • The PFS endpoint is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories.
  • The FACT-Leu-TOI was assessed up to 3 years after study enrolment.
  • There were no statistically significant differences between the two treatment arms.
  • Overall, therefore, there is no advantage or disadvantage for ibrutinib in combination with rituximab with regard to these endpoints.
• Health-related quality of life
  • No data on quality of life are available.
  • The assessment using the FACT-Leu-TOI is classified under the endpoint category of morbidity.
• Side effects
  • Side effects were recorded in both study arms up to 30 days after the end of treatment or 1 day before the start of follow-up therapy.
  • In both the intervention and control arms, 100% of patients experienced an adverse event.
  • No analyses are available for this endpoint.
  • The time-to-event analyses show a statistically significant advantage for ibrutinib in combination with rituximab.
  • With regard to the endpoint of discontinuation due to adverse events, there is a statistically significant difference in favour of ibrutinib + rituximab.
  • In detail, when examining the specific adverse events for the endpoints ‘upper respiratory tract infection (PT, AEs)’, ‘nausea (PT, AEs)’, ‘constipation (PT, AEs)’, ‘vomiting (PT, AEs)’, ‘reduced appetite (PT, AEs)’, ‘pollakiuria (PT, AEs)’, ‘low lymphocyte count (PT, severe AEs)’, ‘low white blood cell count (PT, severe AEs)’, ‘febrile neutropenia (PT, severe AEs)’, “Reduced platelet count (PT, severe AEs)”, and “Hyperglycaemia (PT, severe AEs)” each showed statistically significant differences in favour of ibrutinib in combination with rituximab.
  • For the specific adverse events “bleeding (SMQ bleeding terms [excluding laboratory terms], adverse events)”, “contusion (PT, adverse events)”, “Leucocytosis (PT, severe AEs)” and “Elevated lymphocyte count (PT, severe AEs)”, the event-time analyses each revealed a statistically significant disadvantage for ibrutinib in combination with rituximab compared with FCR.
  • Overall, therefore, in the category of side effects, ibrutinib in combination with rituximab is found to have predominantly advantages compared with treatment with FCR.
• Overall assessment / Conclusion
  • For the assessment of the additional benefit of ibrutinib in combination with rituximab in adult patients with previously untreated chronic lymphocytic leukaemia, for whom treatment with FCR is an option, data are available from a relevant patient population of the ECOG-E12 study, comparing it with FCR for the endpoint categories of mortality, morbidity and side effects.
  • With regard to overall survival, there is a statistically significant advantage with ibrutinib in combination with rituximab compared with FCR.
  • It should be noted, however, that only a very minor number of events had occurred by the time of the second data cut-off.
  • However, despite this limitation, the advantage can be classified as a clear therapeutic improvement due to the magnitude of the effect.
  • In the morbidity category, based on the data collected using the FACT-Leu-TOI, there is no statistically significant difference between the two treatment arms.
  • The data submitted by the pharmaceutical manufacturer for the quality of life category were allocated to the morbidity category in the benefit assessment.
  • Consequently, no evaluable data are available in the quality of life category.
  • For the endpoint category ‘side effects’, advantages are evident in terms of the overall rates of severe side effects and therapy discontinuations due to side effects in the ibrutinib + rituximab arm.
  • In detail, an analysis of specific adverse events also shows predominantly advantages in the intervention arm.
  • It should be noted that, based on the time-to-event analyses, comparative conclusions can only be drawn for the period of the first 9 months following randomisation.
  • No conclusions can be drawn regarding side effects occurring in the longer term on the basis of the event-time analyses.
  • Whilst treatment with ibrutinib is intended to continue until disease progression in the ibrutinib plus rituximab arm, the use of FCR is limited to 6 cycles.
  • Overall, there is therefore a clear advantage in terms of overall survival and, at the same time, predominantly favourable outcomes in the category of side effects.
  • On balance, based on the available data, for ibrutinib in combination with rituximab in adult patients with previously untreated chronic lymphocytic leukaemia who are eligible for FCR therapy, a considerable additional benefit can be inferred compared with FCR combination therapy.

b) Adult patients with previously untreated chronic lymphocytic leukaemia for whom treatment with FCR is not an option

• An additional benefit is not proven for ibrutinib in combination with rituximab for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia for whom FCR therapy is not an option.
• The pharmaceutical manufacturer did not submit any data that would have been suitable for assessing the additional benefit compared with the appropriate comparator therapy.

c) Adult patients with previously untreated chronic lymphocytic leukaemia with a 17p deletion and/or TP53 mutation, or for whom chemo-immunotherapy is not indicated for other reasons

• No additional benefit is proven for ibrutinib in combination with rituximab for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia with a 17p deletion and/or TP53 mutation, or for whom chemo-immunotherapy is not indicated for other reasons.
• The pharmaceutical manufacturer did not submit any data that would have been suitable for assessing the additional benefit compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.