Venetoclax (2) – Venclyxto®

• Clinical trials
  • To demonstrate additional benefit, the pharmaceutical manufacturer has drawn on the results of the pivotal MURANO trial.
  • A total of 391 adult patients with relapsed or refractory CLL, as defined by the iwCLL criteria, were enrolled in the randomised, open-label Phase III trial.

a1) Adult patients with CLL without a 17p deletion and/or TP53 mutation, for whom chemo-immunotherapy is indicated and who have received at least one prior course of treatment – patients for whom bendamustine in combination with rituximab represents the appropriate treatment on an individual basis

• Indication of a minor additional benefit.
• Overall, there is a minor additional benefit in the endpoint category of side effects.
• Taking into account the severity of the disease, a minor additional benefit of venetoclax in combination with rituximab is identified in patient population a1) on the basis of the positive effects.
• The probability of additional benefit is classified in the ‘indication’ category, taking into account the available, single clinical trial.
• mortality
  • overall survival
  • Overall survival differed statistically significantly between the study arms in terms of the p-value based on the pre-specified log-rank test (hazard ratio (HR): 0.32 [95% confidence interval (CI): 0.10; 1.02]; p-value 0.043).
  • Given the minor number of cases included in the analysis of overall survival to date, and taking into account the wide confidence interval of the effect estimator, which includes 1, the advantage of venetoclax in combination with rituximab compared with the appropriate comparator therapy in terms of overall survival cannot currently be quantified.
• morbidity
  • Progression-free survival
  • Progression-free survival differed statistically significantly between the two study arms, in favour of the intervention (HR: 0.11 [95% CI: 0.05; 0.25]; p-value < 0.001).
  • The PFS endpoint is a composite endpoint comprising endpoints from the mortality and morbidity categories.
  • Visual analogue scale EQ-5D
  • In none of the analyses presented is the difference between the study arms statistically significant.
  • EORTC QLQ-C30 symptom scales
  • With regard to the mean difference, a statistically significant difference was found only for the diarrhoea symptom scale, to the detriment of the intervention (mean difference (MD): 10.74 [95% CI: 1.37; 20.10]).
  • B-symptoms
  • Overall, in the morbidity endpoint category, there were neither advantages nor disadvantages associated with venetoclax in combination with rituximab.
• Health-related quality of life
  • Global health status & functional scales EORTC QLQ-C30
  • There is no additional benefit in the quality of life endpoint category.
• Side effects
  • Almost all patients in both study arms experienced an adverse event during the course of their respective treatment (100% vs. 97.0%).
  • Whilst the overall rates were almost identical (37.8% vs. 37.9%), there was a statistically significant difference in favour of venetoclax with rituximab in terms of the time to the first serious adverse event (SAE) (HR 0.39 [95% CI: 0.20; 0.76]; p-value 0.005).
  • Severe adverse events with a CTCAE severity grade of ≥ 3 were observed in 79.7% of patients in the intervention arm and 65.2% of patients in the control arm, after a median of 3.1 and 3.7 months, respectively.
  • Overall, within the ‘side effects’ endpoint category, the findings show exclusively benefits in favour of venetoclax in combination with rituximab. The extent of the improvements is assessed as moderate when viewed as a whole.
• Overall assessment
  • For the benefit assessment of venetoclax in combination with rituximab, results from the MURANO study on overall survival, morbidity, health-related quality of life and side effects are available for the patient population under consideration.
  • Venetoclax in combination with rituximab statistically significantly prolongs overall survival compared with bendamustine in combination with rituximab; however, this is based on only a small number of events to date.
  • With regard to the endpoint categories of morbidity and health-related quality of life, there are no differences between the interventions that warrant consideration.
  • In the endpoint category of side effects, only positive effects of the drug combination under assessment were observed.
  • Taking into account the severity of the disease, a minor additional benefit of venetoclax in combination with rituximab is identified in patient population a1) on the basis of the positive effects.

a2) Adult patients with CLL without a 17p deletion and/or TP53 mutation, for whom chemo-immunotherapy is indicated and who have received at least one prior course of treatment - Patients for whom a treatment other than bendamustine in combination with rituximab represents the most appropriate treatment on an individual basis

• An additional benefit is not proven.
• For the patient population for whom a treatment other than bendamustine in combination with rituximab represents the individually appropriate treatment, no conclusions regarding additional benefit can be drawn, taking the MURANO study into account.
• The additional benefit of venetoclax in combination with rituximab is therefore not proven for patient population a2).

b) Adult patients with CLL with a 17p deletion and/or TP53 mutation, or patients for whom chemo-immunotherapy is not indicated for other reasons and who have received at least one prior course of treatment

• The additional benefit is not proven.
• It is not possible to assess the additional benefit on the basis of the data provided, as the comparison presented between venetoclax plus rituximab and bendamustine plus rituximab does not allow conclusions to be drawn regarding outcomes compared with the appropriate comparator therapy in the patient population under assessment.
• The additional benefit for adult patients with CLL with a 17p deletion and/or TP53 mutation, or for patients for whom chemo-immunotherapy is not indicated for other reasons and who have received at least one prior course of treatment, is therefore not proven.

Courtesy translation only, please refer to the German original.