Ibrutinib (6) – Imbruvica®

• Clinical trials
  • The benefit assessment is based on the results of the ongoing, open-label, randomised iLLUMINATE trial, which compares the combination therapy of ibrutinib plus obinutuzumab with the combination therapy of chlorambucil plus obinutuzumab.

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

• For ibrutinib in combination with obinutuzumab for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL) who are eligible for treatment with fludarabine in combination with cyclophosphamide and rituximab (FCR) is an option, an additional benefit is not proven.
• The pharmaceutical manufacturer did not submit any data that would have been suitable for assessing the additional benefit compared with the appropriate comparator therapy.

b) Adult patients with previously untreated chronic lymphocytic leukaemia (CLL) for whom treatment with fludarabine in combination with cyclophosphamide and rituximab (FCR) is not an option

• mortality
  • The endpoint of overall survival is defined in the iLLUMINATE trial as the time from randomisation to death from any cause.
  • With regard to these endpoints, no statistically significant difference was observed between the two treatment arms (hazard ratio (HR): 1.21; [95% confidence interval (CI): 0.55; 2.68]; p-value = 0.638).
  • At the time of the second data cut-off, there were only a few events in both the ibrutinib arm (n = 15 (20.5 %)) and the control arm (n = 12 (16.7 %)).
  • It should be noted that the results for the overall survival endpoint are not yet particularly meaningful, particularly due to the minor event rates observed to date in the study arms and the relatively short follow-up period.
  • For the endpoint of overall survival, the additional benefit of ibrutinib in combination with obinutuzumab is not proven.
• Morbidity – Progression-free survival (PFS IRC)
  • Progression-free survival, assessed by an independent review committee (IRC), is the primary endpoint of the iLLUMINATE trial.
  • It is defined as the time from randomisation to the onset of disease progression (according to IWCL (International Workshop on Chronic Lymphocytic Leukaemia) criteria) or death.
  • Treatment with ibrutinib in combination with obinutuzumab was associated with significantly longer progression-free survival compared with chlorambucil in combination with obinutuzumab (HR: 0.25; [95% CI: 0.14; 0.46]; p-value < 0.0001).
  • The PFS endpoint is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories.
  • This does not affect the overall conclusion regarding additional benefit.
• quality of life
  • No data on quality of life were collected in the iLLUMINATE study.
• Side effects – Serious adverse events (SAEs)
  • The time-to-event analyses show a statistically significant difference in favour of ibrutinib + obinutuzumab (HR: 0.52; [95% CI: 0.28; 0.97]; p = 0.040).
  • In the ibrutinib arm, 42 patients (57.5%) experienced a SAE, compared with 27 patients (38.0%) in the control arm.
  • There is an effect modification with regard to the characteristic of sex.
• Overall assessment / Conclusion
  • For the assessment of the additional benefit of ibrutinib in combination with obinutuzumab for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL) for whom therapy with fludarabine in combination with cyclophosphamide and rituximab (FCR) is not an option, data from the iLLUMINATE study are available on mortality, morbidity and side effects compared with chlorambucil in combination with obinutuzumab.
  • With regard to overall survival, there is no statistically significant difference between the two treatment arms. An additional benefit for this endpoint is therefore not proven. It should be noted, however, that the results for the endpoint of overall survival are as yet of limited significance, particularly due to the minor event rates observed to date in the study arms and the relatively short follow-up period.
  • With regard to the morbidity category, no clinically relevant difference between ibrutinib + obinutuzumab and chlorambucil + obinutuzumab can be inferred with sufficient certainty based on the health status assessed using the EQ-5D VAS.
  • Data on quality of life were not collected in the iLLUMINATE study.
  • In the category of side effects, ibrutinib + obinutuzumab showed advantages in terms of serious adverse events and severe adverse events (CTCAE grade ≥ 3). In detail, these advantages are particularly evident in the case of acute side effects. However, due to the short follow-up period in the comparator arm, the event-time analyses allow comparative conclusions to be drawn only for the first 6 months of treatment.
  • Overall, a modest additional benefit has therefore been identified for ibrutinib in combination with obinutuzumab in the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL) for whom treatment with fludarabine in combination with cyclophosphamide and rituximab (FCR) is not an option, a minor additional benefit has been identified.
• Overall assessment / Conclusion
  • For the assessment of the additional benefit of ibrutinib in combination with obinutuzumab for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL) for whom treatment with fludarabine in combination with cyclophosphamide and rituximab (FCR) is not an option, data from the iLLUMINATE trial are available on mortality, morbidity and side effects compared with chlorambucil in combination with obinutuzumab.
  • With regard to overall survival, there is no statistically significant difference between the two treatment arms. An additional benefit for this endpoint is therefore not proven. It should be noted, however, that the results for the endpoint of overall survival are as yet not very meaningful, particularly due to the minor event rates observed so far in the study arms and the relatively short follow-up period.
  • With regard to the morbidity category, no clinically relevant difference between ibrutinib + obinutuzumab and chlorambucil + obinutuzumab can be concluded with sufficient certainty based on the health status assessed using the EQ-5D VAS.
  • Data on quality of life were not collected in the iLLUMINATE study.
  • In the category of side effects, ibrutinib + obinutuzumab showed advantages in terms of serious adverse events and severe adverse events (CTCAE grade ≥ 3). In detail, these advantages are particularly evident in the case of acute side effects. However, due to the short follow-up period in the comparator arm, the event-time analyses allow comparative conclusions to be drawn only for the first 6 months of treatment.
  • Overall, a modest additional benefit has therefore been identified for ibrutinib in combination with obinutuzumab in the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL) for whom treatment with fludarabine in combination with cyclophosphamide and rituximab (FCR) is not an option, a minor additional benefit has been identified.

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

• For ibrutinib in combination with obinutuzumab for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL), with a 17p deletion and/or TP53 mutation, or for whom chemo-immunotherapy is not indicated for other reasons, an additional benefit is not proven.
• The pharmaceutical manufacturer presented a descriptive comparison of individual study arms. To this end, it drew on the iLLUMINATE study for the combination under investigation, ibrutinib + obinutuzumab. For the appropriate comparator therapy, ibrutinib monotherapy, he included the studies by Burger 2019, Woyach 2018 and Ahn 2018.
• As described by the pharmaceutical manufacturer, there is no dramatic effect that would allow an additional benefit to be established given the heterogeneous study designs involved.

Courtesy translation only, please refer to the German original.