Idelalisib (1) – Zydelig®

• Clinical trials
  • The GS-US-312-0116 trial is a randomised, double-blind, phase III trial investigating the efficacy of idelalisib in combination with rituximab in patients with previously treated chronic lymphocytic leukaemia.
  • The aim of study 101-08 was to investigate the efficacy and safety of idelalisib in combination with rituximab for the treatment of elderly, treatment-naïve patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL).

a) Patients with relapsed 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).

b) Patients with relapsed 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
  • 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).
  • Overall survival in the intervention and control groups differed significantly at the time of the second interim analysis (HR = 0.28; 95% CI [0.11; 0.69]; p = 0.003). A median survival time could not be determined in either the treatment arm or the control arm due to the minor number of deaths.
  • The data on overall survival must be regarded as immature due to the short duration of the study compared with life expectancy.
  • Due to the crossover of a significant number of patients from 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 disease progression (evidence of progression or recurrence) according to IWCLL criteria or death (regardless of cause), whichever occurred first.
  • The PFS endpoint is a composite endpoint comprising endpoints from the mortality and morbidity categories.
  • At the time of the second interim analysis, the median PFS was 5.5 months with rituximab; with the combination of idelalisib and rituximab, the median PFS had not yet been reached (HR = 0.18; 95% CI [0.10; 0.32]; p < 0.001).
  • The data on progression-free survival are to be regarded as immature due to the short duration of the study compared with the effects in the active arm.
• 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 to the study medication.
  • At the time of the second interim analysis, the overall response rate was 74.5% in the active treatment arm and 14.5% in the control arm (odds ratio = 17.28; 95% CI [8.66; 34.46]; p < 0.001).
• Side effects
  • Adverse events (AEs) of CTCAE grade ≥ 3 occurring in ≥ 2% of patients:
  • With regard to the assessment of the side effects endpoint, no conclusion can be drawn in the present context regarding the extent of any additional benefit.
  • Idelalisib has hepatotoxic potential and may, in isolated cases, cause severe diarrhoea or colitis. However, these adverse effects were reversible if treatment was discontinued and, in the case of diarrhoea or colitis, symptomatic treatment with glucocorticoids was also administered.
  • Given the minor number of patients treated with the active ingredient (INN) to date and the short observation period compared with the hypothetical duration of treatment, it must be assumed that the adverse effects of treatment with idelalisib have so far only been partially documented.
• Overall review
  • The comparator used in the control arm of the GS-US-312-0116 does not reflect the ‘best supportive care’ comparator therapy determined by the G-BA as the appropriate comparator; however, it is still possible to make a qualitative assessment of additional benefit from the study results, taking into account the existing limitations.
  • The results of the registration trial show a significant advantage of treatment with idelalisib and rituximab compared with the comparator in terms of overall survival. However, the data on overall survival must be regarded as immature.
  • The differences between the active treatment arm and the control arm for the endpoints PFS and overall response rate are, however, pronounced in a way that would not have been expected in a patient population defined in this manner, and thus support the existence of a qualitative additional benefit for the endpoint of overall survival.
  • 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.

c) Patients with refractory CLL for whom chemotherapy or treatment with ofatumumab is indicated

• For patients in patient population 1c, 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).

d) Patients with refractory CLL for whom chemotherapy or treatment with ofatumumab is not indicated

• For patients in patient population 1d, 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, SGB V).

2) For first-line treatment of chronic lymphocytic leukaemia (CLL) in the presence of a 17p deletion or a TP53 mutation in patients who are unsuitable for chemoimmunotherapy

• For patients in Therapeutic Indication 2, there is a hint of a non-quantifiable additional benefit compared with the appropriate comparator therapy.
• The G-BA classifies the extent of the non-quantifiable additional benefit of idelalisib 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’, but this is non-quantifiable because the available scientific data do not permit this.
• Morbidity – Progression-free survival (PFS)
  • Results of the GS-US-312-0116 study for the 17p-deletion or TP53-mutation patient population:
• Morbidity – Overall Response Rate (ORR)
  • Results from the GS-US-312-0116 trial for the 17p deletion or TP53 mutation patient population:
• Overall view
  • For patients with chronic lymphocytic leukaemia and a 17p deletion or TP53 mutation who are unsuitable for first-line treatment with chemoimmunotherapy, there are no relevant data available for a comparison of idelalisib with the appropriate comparator therapy, best supportive care.
  • A subgroup analysis shows, for patients with 17pdeletion or TP53 mutation, which the G-BA considers to be of particular relevance to healthcare provision for these study participants classified as high-risk patients.
  • 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 benefit is non-quantifiable because the available scientific data do not permit this.

3) Patients with follicular lymphoma (FL) that is refractory to two previous lines of treatment

• For patients in therapeutic indication 3, additional benefit compared with the appropriate comparator therapy is deemed not proven.
• Reasoning: The required evidence has not been submitted (Section 35a(1), fifth sentence, of Book V of the Social Code).

Courtesy translation only, please refer to the German original.