Ibrutinib (5) – Imbruvica®

• Clinical trials
  • To demonstrate the additional benefit of ibrutinib in combination with bendamustine and rituximab for the treatment of adult patients with CLL who have received at least one prior course of treatment, the pharmaceutical manufacturer has submitted the results of the HELIOS trial (Study PCI32765CLL3001).
  • This randomised, double-blind registration trial – which remained double-blind until the first interim analysis – investigated the efficacy and safety of the combination of ibrutinib, bendamustine and rituximab compared with the active comparator, bendamustine in combination with rituximab.

a) Patients with at least two prior lines of treatment for whom bendamustine in combination with rituximab represents the individually optimised treatment

• mortality
  • overall survival
  • For overall survival, there was no statistically significant difference between the study arms in the overall study population (hazard ratio (HR): 0.671 [95% confidence interval (CI): 0.442; 1.019]; p-value = 0.0595).
  • In the patient population used for this analysis, there was a statistically significant advantage in favour of the triple combination (HR: 0.43 [95% CI: 0.21; 0.89]; p = 0.022); the median time to all-cause death was 34.5 months in the control arm and had not yet been reached in the intervention arm as at the data cut-off date of 1 October 2015.
  • Due to the high proportion of patients in the control arm (23 patients at the second data cut-off, corresponding to 43%) who switched treatment to ibrutinib in combination with bendamustine and rituximab, the endpoint is subject to a high potential for bias.
  • For the endpoint category of mortality, based on the results presented for the patient population a), there is overall a considerable additional benefit from the addition of ibrutinib to the combination of bendamustine and rituximab.
• morbidity
  • Progression-free survival (PFS)
  • In the HELIOS study, the endpoint of progression-free survival was defined as the time from randomisation to disease progression according to IWCLL criteria or death from any cause.
  • PFS (as assessed by the Independent Review Committee) was statistically significantly prolonged in the ibrutinib treatment group compared with the control group at the first data cut-off (median not yet reached vs. 8.6 months; HR: 0.243 [95% CI: 0.139; 0.424]; p < 0.0001).
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint.
  • EORTC-QLQ-C30 (symptom scales)
  • No statistically significant, clinically relevant difference was found for any symptom scale of the EORTC-QLQ-C30, neither in terms of improvement nor deterioration.
  • EQ-5D-5L Visual Analogue Scale
  • Taking into account the time to deterioration or time to improvement by 7 mm or 10 mm on the EQ-5D-5L visual analogue scale, the HELIOS study found no statistically significant differences between the treatment arms in the patient population analysed.
  • FACIT-Fatigue
  • For the fatigue endpoint, the results of the FACIT-Fatigue were analysed in terms of the time to a change of 3 points compared with the baseline value.
  • There were no statistically significant differences between the treatment arms, neither for an improvement of 3 points (HR: 0.96 [95% CI: 0.60; 1.55]; p = 0.869) nor for a 3-point worsening (HR: 1.23 [95% CI: 0.71; 2.12]; p = 0.456) were the differences between the treatment arms statistically significant.
  • In summary, within the morbidity endpoint category, there was no added benefit of ibrutinib in combination with bendamustine and rituximab compared with bendamustine and rituximab alone, neither for the symptom scales of the EORTC-QLQ-C30, nor with regard to fatigue, which was assessed again using the FACIT questionnaire, does ibrutinib in combination with bendamustine and rituximab offer any additional benefit compared with bendamustine and rituximab alone.
• Health-related quality of life
  • EORTC-QLQ-C30 (functional scales)
  • Health-related quality of life was assessed in the HELIOS trial using the functional scales of the EORTC-QLQ-C30.
  • A statistically significant difference in favour of the triple combination was observed only for the time to deterioration in social functioning (HR: 0.54 [95% CI: 0.29; 0.996]; p = 0.049).
  • None of the other functional scales showed a statistically significant difference between the treatment arms, either in terms of time to improvement or time to deterioration.
  • Overall, there is an additional benefit of ibrutinib in combination with bendamustine and rituximab in the quality of life endpoint category with regard to social functioning.
• Side effects
  • Adverse events (AEs)
  • An adverse event was recorded for almost all patients in the relevant patient population in both arms of the HELIOS trial (intervention arm: 98.1%, control arm: 98.1%).
  • Serious adverse events (SAEs)
  • There was no statistically significant difference between the treatment groups in terms of serious adverse events (HR: 0.96 [95% CI: 0.57; 1.62]; p = 0.874).
  • Severe AEs (CTCAE Grade 3/4)
  • With regard to the time to onset of severe adverse events of CTCAE grade 3 or 4, the difference between the treatment arms was also not statistically significant (HR: 0.67 [95% CI: 0.44; 1.02]; p = 0.064).
  • Discontinuation due to AEs
  • The median time for therapy discontinuation due to an adverse event did not differ statistically significantly between the treatment arms (HR: 0.39 [95% CI: 0.15; 1.01]; p = 0.052).
  • As the overall results did not show any statistically significant differences between the treatment arms, or were not sufficiently interpretable, additional benefit of the triple combination is not proven for the endpoint category of side effects.
• Conclusion
  • In the overall analysis of the endpoints considered, the results for ibrutinib in combination with bendamustine and rituximab are exclusively positive.
  • In the endpoint category of mortality, there were clear advantages for ibrutinib over the appropriate comparator therapy.
  • In the ‘quality of life’ endpoint category, there is a single positive result regarding social functioning.
  • In view of the positive results mentioned, the G-BA concludes that there is considerable additional benefit for ibrutinib in combination with bendamustine and rituximab.

b) Patients who have received prior treatment and patients for whom a therapy other than bendamustine in combination with rituximab represents the individually optimised treatment

• For patients who have received prior treatment and for patients for whom a therapy other than bendamustine in combination with rituximab represents the individually optimised treatment, additional benefit is not proven.
• As the benefit assessment was based exclusively on results from the HELIOS study comparing the treatment with bendamustine in combination with rituximab, no conclusions can be drawn regarding the additional benefit compared with the other treatment options also included in the defined appropriate comparator therapy.

Courtesy translation only, please refer to the German original.