Venetoclax (5) – Venclyxto®

• Clinical trials
  • The benefit assessment of the active ingredient venetoclax in combination with HMA is based on the ongoing, pivotal Viale-A trial.
  • This is a double-blind, randomised, controlled, multicentre Phase III trial comparing the combination therapy of venetoclax and azacitidine with placebo plus azacitidine.

Adults with newly diagnosed acute myeloid leukaemia (AML) who are not suitable for intensive chemotherapy

• Overall, the G-BA concludes that, for the treatment of adults with newly diagnosed de novo or secondary acute myeloid leukaemia (AML) who are not eligible for standard induction chemotherapy, there is a hint of considerable additional benefit for venetoclax in combination with HMA.
• mortality
  • In the Viale-A trial, overall survival was assessed as a co-primary endpoint.
  • Treatment with venetoclax plus azacitidine results in a statistically significant advantage in overall survival compared with placebo plus azacitidine.
  • Given the known poor prognosis for patients in this therapeutic indication, the extent of this advantage is considered a significant improvement in overall survival.
• Morbidity – Transfusion independence
  • In the Viale-A study, the endpoint ‘transfusion independence’ is defined as the proportion of patients who were transfusion-independent (no transfusions of either platelets or red blood cells) for ≥ 8 weeks during the treatment phase, i.e. between the first dose of the study medication and one of the following events: 30 days after the last dose of the study medication, death, or the start of subsequent therapy (whichever occurs first).
  • With regard to the analyses of the various periods of transfusion-free survival, the G-BA considers a transfusion-free period of ≥ 24 weeks to be the relevant timeframe for assuming long-term avoidance of transfusions (transfusion independence).
  • Based on the event-time analysis for complete transfusion-free survival (red blood cell and platelet transfusions) over ≥ 24 weeks, there is a statistically significant advantage for venetoclax in combination with azacitidine compared with placebo plus azacitidine.
  • Given that, in the present therapeutic indication, the administration of red blood cell and platelet transfusions is used to pursue palliative, highly individualised treatment goals are pursued, the positive effect of venetoclax in combination with azacitidine – taking into account the magnitude of the effect and the comments made by clinical experts during the commenting procedure for this assessment – is considered a relevant finding for the present evaluation, despite the uncertainties described above.
• Morbidity – Remission
  • Remission was the co-primary endpoint in the Viale-A study.
  • The endpoint was operationalised as the occurrence of a complete remission (CR) or a complete remission with incomplete haematological recovery (CRi).
  • The CR/CRi endpoint is therefore classified in this assessment as an endpoint of unclear relevance and is presented only as supplementary information.
• Morbidity – Symptoms (EORTC QLQ-C30)
  • The collection of patient-reported endpoints in the Viale-A study is welcomed.
  • However, due to the minor response rates in both treatment arms as early as cycle 3 – the first assessment point during treatment with the study medication – the analyses submitted by the pharmaceutical manufacturer are, however, deemed unusable and are not taken into account for this benefit assessment.
• quality of life
  • Health-related quality of life is assessed in the Viale-A study using the functional scales and the global health status scale (overall assessment) of the cancer-specific EORTC QLQ-C30 questionnaire.
  • Taking into account the comments in the ‘Symptoms’ section regarding the low response rates, the analyses of the quality of life submitted by the pharmaceutical manufacturer are not used for this benefit assessment.
  • For the quality of life endpoint category, no advantages or disadvantages of venetoclax + azacitidine compared with placebo + azacitidine can be identified.
• Side effects
  • The overall rates of side effects presented here include not only treatment-related AEs but also AEs that may be attributable to progression of the underlying disease.
  • There are no statistically significant differences between the treatment arms for SAE, severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs.
  • For the specific AEs ‘contusion’ (AE) and ‘injury, poisoning and procedural complications’ (severe AEs), a statistically significant advantage was observed in favour of venetoclax + azacitidine compared with placebo + azacitidine.
  • For the endpoint of neutropenia (comprising neutropenia, low neutrophil count, febrile neutropenia, agranulocytosis, neutropenic infection, and neutropenic sepsis [severe AEs]), there was a statistically significant difference in favor of venetoclax + azacitidine compared with placebo + azacitidine.
  • In the overall analysis of the results on side effects, there were no differences between the treatment arms in the endpoints SAE, severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs that were relevant to the benefit assessment.
• Overall assessment
  • For the assessment of the additional benefit of venetoclax in combination with hypomethylating agents (HMA), results are available from the double-blind, randomised, controlled Viale-A study for the endpoint categories of mortality, morbidity, quality of life and side effects.
  • For overall survival, there is a statistically significant difference between the treatment arms, which is assessed as a clear advantage for venetoclax in combination with HMA.
  • In the overall analysis of the morbidity results, there is an advantage of venetoclax in combination with HMA for the endpoint of transfusion independence.
  • No usable data are available for the quality of life endpoint category.
  • Based on the results regarding side effects, there are no differences between the treatment arms that are relevant to the benefit assessment for the endpoints of SAE, severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs.
  • Overall, the G-BA concludes that, for the treatment of adults with newly diagnosed de novo or secondary acute myeloid leukaemia (AML) who are not eligible for standard induction chemotherapy, Venetoclax in combination with HMA offers a considerable additional benefit.

Courtesy translation only, please refer to the German original.