Ibrutinib (3) – Imbruvica®

• Clinical trials
  • The randomised, open-label Phase III trial PCYC-1112-CA investigated the efficacy and safety of ibrutinib (195 patients) compared with the active comparator ofatumumab (196 patients), both in combination with best supportive care.

I1a) Therapeutic indication I: Chronic lymphocytic leukaemia – patients with relapsed or refractory CLL for whom chemotherapy is indicated

• For patients with relapsed or refractory CLL for whom chemotherapy is indicated, additional benefit is not proven.

I1b) Therapeutic indication I: Chronic lymphocytic leukaemia – patients with relapsed or refractory CLL for whom chemotherapy is not indicated

• For patients with relapsed or refractory CLL for whom chemotherapy is not indicated, there is a hint of a non-quantifiable additional benefit.
• The G-BA therefore classifies the extent of the additional benefit of ibrutinib in this population as non-quantifiable, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the disease. An additional benefit exists but is non-quantifiable because the scientific evidence does not permit this.
• Consequently, the PCYC-1112-CA study provides, at most, a hint of additional benefit for the patient population in question.
• mortality
  • Median overall survival was not reached at the relevant second data cut-off point in the PCYC-1112-CA study in either the intervention or control arm. However, for the patient population of double-refractory patients, a statistically significant difference was observed between the two arms with regard to the Kaplan-Meier curves (hazard ratio (HR) 0.19 [95% confidence interval (CI): 0.06; 0.62], p = 0.002).
  • Based on these considerations, and taking into account the uncertainties arising from the patient population being addressed only approximately and the treatment in the control arm not corresponding to the appropriate comparator therapy, the G-BA concludes that ibrutinib offers a non-quantifiable additional benefit for the endpoint of mortality.
• morbidity
  • Based on the data submitted, it is not possible to assess the extent to which, or in what direction, the results for the morbidity endpoints may be biased due to the inadequate implementation of the appropriate comparator therapy. As it is unclear whether the results are biased in favour of or against ibrutinib, no conclusion regarding additional benefit can be drawn.
• Health-related quality of life
  • For the health-related quality of life endpoint category, no reliable conclusions regarding added benefit compared with the appropriate comparator therapy can be drawn due to the use of ofatumumab in the comparator arm of the PCYC-1112-CA and the associated high potential for bias, no reliable conclusions regarding additional benefit compared with the appropriate comparator therapy can be drawn, just as is the case for the morbidity endpoint category.
• Side effects
  • The results for the endpoint category ‘side effects’ cannot be used for the assessment either. The direction of the potential for bias in the results cannot be clearly assessed.
  • In the ibrutinib arm of the PCYC-1112-CA trial, a higher proportion of double-refractory patients experienced adverse events with a severity of CTCAE ≥ 3 (67.6% vs. 54.2%). Differences were particularly evident with regard to severe neutropenia (23.5% vs. 12.5%) and severe pneumonia (17.6% vs. 4.2%).
• Overall view
  • The results on overall survival, which are of limited interpretative value and show advantages for ibrutinib, are offset by potential disadvantages in terms of symptoms, health-related quality of life and adverse events.
  • Taking the results as a whole, it is not considered that the potential disadvantages of ibrutinib at the endpoints for symptoms, quality of life and, in particular, adverse events would offset the statistically significant advantage in overall survival.

I2) Therapeutic indication I: Chronic lymphocytic leukaemia – first-line treatment of CLL in patients with a 17p deletion or a TP53 mutation who are unsuitable for chemoimmunotherapy

• For patients receiving first-line treatment for CLL with a 17p deletion or a TP53 mutation who are unsuitable for chemoimmunotherapy, there is a hint of a non-quantifiable additional benefit.
• The G-BA classifies the extent of the additional benefit of ibrutinib in first-line treatment of CLL in patients with a 17p deletion or a TP53 mutation who are unsuitable for chemoimmunotherapy as non-quantifiable, based on 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 treating the disease. An additional benefit exists, but is non-quantifiable because the scientific evidence does not permit this.
• Furthermore, from the PCYC-1112-CA study, at most a hint of additional benefit can be inferred for the patient population relevant to the assessment.

IIa) Therapeutic indication II: Mantle cell lymphoma – patients with relapsed or refractory mantle cell lymphoma – for patients for whom temsirolimus represents the appropriate treatment option on an individual basis

• For patients with relapsed or refractory mantle cell lymphoma, there is an indication of considerable additional benefit.
• The G-BA classifies the extent of the additional benefit of ibrutinib as considerable, based on 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 treating the disease.
• However, classifying the extent of the additional benefit as ‘major’ is not justified, as, in particular, no survival benefit could be demonstrated and the results regarding health status do not reach a level that could be considered major.
• mortality
  • With regard to overall survival, there was no statistically significant difference between the study arms in the overall population (HR 0.76 [95% CI: 0.53; 1.09], p = 0.132).
  • Overall, therefore, there is no additional benefit of ibrutinib for the endpoint category of mortality.
• Morbidity – Progression-free survival (PFS)
  • PFS was statistically significantly prolonged in the ibrutinib treatment group compared with the control group (median 14.6 months vs. 6.2 months; HR: 0.43 [0.32; 0.58], p < 0.0001).
• Morbidity – Visual Analogue Scale of the EQ-5D-5L
  • With regard to time to deterioration, there is a statistically significant advantage of ibrutinib, both when using a threshold of 7 scale points (HR 0.47 [95% CI: 0.33; 0.68], p < 0.001) and, to a lesser extent, when using the non-validated threshold of 12 points (HR 0.38 [95% CI: 0.25; 0.57], p < 0.001).
  • The median time to a deterioration of 7 scale points in the ibrutinib arm of the study was 48 weeks, whereas in the temsirolimus arm this occurred after a median of 9.1 weeks.
• Health-related quality of life – FACT-Lym
  • For the FACT-LymS lymphoma subscale, the time to improvement whilst on ibrutinib was statistically significantly shorter for both the lower and upper thresholds, and the time to deterioration was statistically significantly longer for both thresholds in favour of ibrutinib.
  • Overall, significant differences in favour of ibrutinib were observed for the quality of life endpoint category, which are associated with major improvements for patients.
• Side effects – Adverse events (AEs)
  • An adverse event was recorded for almost all patients in both arms of the MCL3001 study (ibrutinib: 99.3 per cent, temsirolimus: 99.3 per cent).
• Side effects – Serious adverse events (SAEs)
  • For the overall population, a statistically significant difference in favour of ibrutinib was observed with regard to serious adverse events (HR: 0.53 [95% CI: 0.38; 0.74], p < 0.001).
• Side effects – Discontinuation due to AEs
  • In the ibrutinib arm of the MCL3001 trial, 18.5% of patients discontinued study treatment, compared with 25.0% in the temsirolimus arm. The median time to discontinuation has not yet been reached in either arm, but there is a statistically significant difference in favour of ibrutinib (HR 0.40 [95% CI: 0.17; 0.92], p = 0.031).
• Side effects – severe AEs (CTCAE Grade 3/4)
  • Adverse events with a CTCAE severity grade of 3 or 4 occurred in significantly fewer patients and at a significantly later stage during treatment with ibrutinib (HR 0.28 [95% CI: 0.20; 0.39], p < 0.001).
• Overall assessment
  • Taking an overall view of the endpoints considered, the results for ibrutinib in the indication of relapsed or refractory mantle cell lymphoma are exclusively positive.
  • In view of the positive results in the endpoint categories of morbidity, quality of life and side effects, whilst taking into account the lack of evidence of an advantage in terms of overall survival, the G-BA concludes that ibrutinib offers a considerable additional benefit.

IIb) Therapeutic indication III: Waldenström’s macroglobulinaemia – patients with relapsed or refractory mantle cell lymphoma – for patients for whom temsirolimus is not the appropriate treatment option on an individual basis

• An additional benefit is not proven.

III) Patients with Waldenström’s macroglobulinaemia who have received at least one prior course of treatment, or as first-line therapy for patients who are not suitable for chemo-immunotherapy

• For patients with Waldenström’s macroglobulinaemia who have received at least one prior course of treatment, or as first-line treatment for patients who are not suitable for chemo-immunotherapy, additional benefit is not proven.

Courtesy translation only, please refer to the German original.