Idelalisib (2) – Zydelig®

• Clinical trials
  • The GS-US-312-0116 trial was a randomised, double-blind, multicentre Phase III trial that investigated the efficacy and safety of idelalisib in combination with rituximab in patients with previously treated chronic lymphocytic leukaemia.

1a) Patients with relapsed or refractory CLL for whom chemotherapy is indicated

• For patients in patient population 1a, additional benefit compared with the appropriate comparator therapy is deemed not proven.
• Reason: The required evidence has not been provided (Section 35a(1), fifth sentence, of Book V of the Social Code).

1b) Patients with relapsed or refractory CLL for whom chemotherapy is not indicated

• For patients in patient population 1b, there is a hint of a non-quantifiable additional benefit compared with the appropriate comparator therapy.
• The G-BA classifies the extent of the additional benefit of idelalisib as non-quantifiable 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. There is a hint of an additional benefit compared with the appropriate comparator therapy (best supportive care); however, this benefit is non-quantifiable because the available scientific data do not permit this.
• Mortality – Overall survival
  • The secondary endpoint of overall survival was defined as the time (in months) between the day of randomisation and death (regardless of the cause of death).
  • The second interim analysis (data cut-off 9 October 2013) showed a significant difference in overall survival between the intervention and control groups (HR = 0.28; 95% CI [0.11; 0.69]; p = 0.003), albeit based on a minor number of deaths.
  • The results of the final data cut-off on 20 April 2014 confirm the findings of the second interim analysis (HR = 0.34; 95% CI [0.19; 0.60]; p < 0.001).
  • Due to the change in treatment for a significant number of patients in the control arm, it is likely that the results are biased, which could lead to an underestimation of the treatment effect.
• Morbidity – Progression-free survival (PFS)
  • The primary endpoint, PFS, was defined as the time (in months) from randomisation to the occurrence of a PFS event. PFS events are defined as disease progression (evidence of progression or recurrence) according to IWCLL criteria or death (regardless of cause), whichever occurred first.
  • The second interim analysis (data cut-off 9 October 2013) showed a significant difference in progression-free survival between the intervention and control groups (HR = 0.18; 95% CI [0.10; 0.32]; p < 0.001).
  • The results of the final data cut-off on 20 April 2014 also show a statistically significant difference (HR = 0.15; 95% CI [0.09; 0.24]; p < 0.001).
  • The PFS endpoint is a composite endpoint comprising endpoints from the mortality and morbidity categories. The ‘mortality’ component of the endpoint is already assessed as a standalone endpoint via the secondary endpoint of overall survival. The ‘disease progression’ component of morbidity was assessed for PFS not only on the basis of symptoms, but primarily using imaging and laboratory procedures.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. The overall conclusion regarding additional benefit remains unaffected by this.
• Morbidity – Overall Response Rate (ORR)
  • The secondary endpoint, overall response rate, was defined as the proportion of patients who demonstrated a complete or partial response.
  • This was assessed not only on the basis of symptoms, but primarily using imaging and laboratory procedures. The overall response rate is therefore not classified as a patient-relevant endpoint.
  • At the time of the second data cut-off, the overall response rate was 74.5% in the treatment arm and 14.5% in the control arm (odds ratio = 17.28; 95% CI [8.66; 34.46]; p < 0.001).
  • The final data cut-off shows an overall response rate of 83.6% in the active treatment arm and 15.5% in the control arm. The difference is statistically significant (odds ratio = 27.76; 95% CI [13.40; 57.49]; p < 0.001).
• Overall assessment
  • The comparator used in the control arm of the GS-US-312-0116 does not reflect the appropriate comparator therapy – ‘best supportive care’ – as determined by the G-BA; however, it is still possible to qualitatively determine an additional benefit from the study results, taking into account the existing limitations.
  • Although the G-BA considers rituximab monotherapy – which is not authorised for this therapeutic indication – to be inappropriate in terms of the expected therapeutic success, it does not regard this as under-treatment in relation to the appropriate comparator therapy.
  • Furthermore, there remains uncertainty as to whether the inclusion criteria for the patient population 1b of the GS-US-312-0116 study are sufficiently precise.
  • As at the data cut-off date of 9 October 2013, the results of the registration trial indicate a significant advantage in terms of overall survival for treatment with idelalisib and rituximab compared with the comparator. The actual survival benefit could not be determined due to the minor number of deaths; the significant advantage in overall survival is derived from the hazard ratio of the Kaplan-Meier curves.
  • However, quantification of the additional benefit of idelalisib is once again not possible for patient population 1b due to the failure to implement the comparator therapy and the methodological limitations described.
  • With regard to the assessment of the endpoint ‘side effects’, no conclusion can be drawn in the present context regarding the extent of any additional benefit, particularly due to the differing treatment durations in the two study arms.
  • An overall review of the results of the marketing authorisation trial GS-US-312-0116 provides a hint of additional benefit compared with the appropriate comparator therapy, best supportive care; however, this additional benefit is non-quantifiable because the available scientific data do not permit this.

2) Continuation of treatment in patients with a 17p deletion or a TP53 mutation who were unsuitable for chemoimmunotherapy and in whom first-line treatment with idelalisib had already been initiated

• For patients falling within Therapeutic Indication 2, additional benefit compared with the appropriate comparator therapy is deemed not proven.
• Reason: The required evidence has not been submitted (Section 35a(1), fifth sentence, of Book V of the Social Code [SGB V]).
• With regard to the continuation of treatment in patients with a 17p deletion or a TP53 mutation who were unsuitable for chemoimmunotherapy and in whom first-line treatment with idelalisib had already been initiated, there are no relevant data available for a comparison of idelalisib with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.