Ixazomib (1) – Ninlaro®

• Clinical trials
  • Study C16010 is a randomised, double-blind, multicentre Phase III trial in which ixazomib in combination with lenalidomide and dexamethasone was compared with placebo in combination with lenalidomide and dexamethasone.

adult patients with multiple myeloma who have received at least one prior course of treatment

• For adult patients with multiple myeloma who have received at least one prior course of treatment, there is a non-quantifiable additional benefit.
• An additional benefit exists in accordance with Section 35a(1), sentence 10, first half-sentence, of SGB V, but it is non-quantifiable because the scientific evidence does not permit this.
• mortality
  • Three interim analyses and one final analysis are planned for overall survival.
  • The results of the first two interim analyses on overall survival are available; these did not show any statistically significant difference between the two treatment arms (data cut-off 30 October 2014: Hazard Ratio (HR) = 0.90; 95% confidence interval (CI) [0.62; 1.32]; p = 0.59; data cut-off 15 July 2015: HR = 0.87; 95% CI [0.64; 1.18]; p = 0.36).
  • Median overall survival had not been reached at the time of either interim analysis.
  • More mature and therefore more meaningful data will be available with the planned third interim analysis (66% data maturity) and the final analysis of overall survival (expected in the fourth quarter of 2017 and the first quarter of 2020, respectively).
• Morbidity – Progression-free survival
  • For the progression-free survival (PFS) endpoint, an interim analysis (after 262 events) and a final analysis (after 365 events) were planned.
  • At the time of the first interim analysis (data cut-off 30 October 2014), a statistically significant advantage in favour of ixazomib compared with the control arm was observed (HR: 0.74; 95% CI [0.59; 0.94]; p = 0.012), with the median PFS on ixazomib being extended by 5.9 months compared with the control arm (median PFS 20.6 months vs. 14.7 months in the intervention vs. control arm).
  • In the second interim analysis (data cut-off 12 July 2015), the effect of ixazomib on PFS between the two study arms was minor, at 4.1 months in favour of ixazomib, and was no longer statistically significant (HR: 0.82; 95% CI [0.67; 1.00]; p = 0.054; median PFS 20.0 months vs. 15.9 months in the intervention arm vs. the control arm).
  • PFS was defined as the time from randomisation to the date of the first documented disease progression (as defined by the International Myeloma Working Group, IMWG) or the patient’s death, regardless of the cause of death – whichever occurred first.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. This does not affect the overall conclusion regarding the extent of the additional benefit.
• quality of life
  • Health-related quality of life was assessed every four weeks until disease progression using selected scales from the EORTC QLQ-C30 and EORTC QLQ-MY20 instruments.
  • No significant difference between the treatment arms was observed for either scale at any assessment time point.
  • Due to the low response rate relative to the expected number of responses – which cannot be explained by mortality rates or other verifiable reasons – the results for this endpoint are not usable.
  • During the commenting procedure, the pharmaceutical manufacturer submitted responder analyses for the pooled study population (ITT and CCS) for both questionnaires with a MID of ≥ 10 points, which showed a significant improvement with ixazomib in the ‘future prospects’ subscale of the EORTC QLQ-MY20 at the end of treatment.
  • However, due to the minor response rate relative to the expected number of responses at the end of treatment, these analyses are not valid.
• Side effects
  • Safety analyses were conducted for adverse events (AEs) from the administration of the first study medication up to 30 days after administration of the last study medication, based on the safety population, i.e. patients who received at least one dose of the study medication.
  • In both arms, almost every study participant experienced at least one adverse event.
  • The incidence rates for serious AEs, severe AEs (CTCAE grade ≥ 3) and discontinuations due to AEs were comparable in both study arms, and no statistically significant difference between the two treatment arms was observed.
  • It is not clear from the analyses of all adverse events in the dossier, nor from the documents submitted by the pharmaceutical manufacturer during the commenting procedure, to what extent the analysis also includes events associated with progression of the underlying disease.
• Overall assessment
  • To assess the extent of the additional benefit of ixazomib in combination with lenalidomide and dexamethasone for patients with multiple myeloma who have received at least one prior line of treatment, results on mortality (overall survival), morbidity, health-related quality of life and side effects from the Phase III RCT C16010, which formed the basis for marketing authorisation, comparing the treatment with placebo in combination with lenalidomide and dexamethasone.
  • For the patient-relevant endpoints in the categories of mortality (overall survival), morbidity (BPI-SF and EQ-5D) and health-related quality of life (EORTC-QLQ-C30 and EORTC-QLQ-MY20), no statistically significant differences were observed between the two treatment arms.
  • Side effects were also comparable between the two treatment arms and showed no statistically significant differences – with the exception of skin and subcutaneous tissue disorders and eye disorders, which showed a statistically significant effect to the detriment of ixazomib.
  • This benefit assessment is based on the two interim analyses of overall survival available to date, with data still immature (data maturity 22% and 35%). A definitive assessment of the overall survival endpoint will only be possible at the time of the final analysis.
  • The G-BA classifies the extent of the non-quantifiable additional benefit of ixazomib on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.

Courtesy translation only, please refer to the German original.