Glasdegib (1) – Daurismo®

• Clinical trials
  • For the benefit assessment of the active ingredient glasdegib, the pharmaceutical manufacturer submitted the pivotal, open-label Phase Ib/II trial B1371003.

Adult patients with newly diagnosed de novo or secondary acute myeloid leukaemia (AML) who are not eligible for standard induction chemotherapy

• Consequently, the G-BA concludes that, in the treatment of adult patients with newly diagnosed de novo or secondary acute myeloid leukaemia (AML) who are not eligible for standard induction chemotherapy, glasdegib in combination with LDAC offers a considerable additional benefit compared with LDAC monotherapy.
• For the reasons stated, the certainty of the evidence for the established additional benefit is classified as ‘hint’.
• mortality
  • In the B1371003 study, overall survival was assessed as the primary endpoint.
  • Treatment with glasdegib + LDAC results in a statistically significant advantage in overall survival compared with LDAC alone.
  • The extent of this advantage is assessed as a significant improvement in overall survival, particularly given the known poor prognosis for patients in the therapeutic indication.
• Morbidity – Transfusion independence
  • In the B1371003 study, the endpoint ‘transfusion independence’ is defined as the proportion of patients achieving transfusion independence for ≥ 8, ≥ 12, ≥ 16, ≥ 20 and ≥ 24 weeks during the treatment phase; that is, patients were not permitted to receive any transfusions (platelet, red blood cell, granulocyte or whole blood transfusions) during the defined consecutive periods.
  • With regard to the analyses of the various periods of transfusion-free status, 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).
  • The results for the endpoint of transfusion independence are presented only as supplementary information, taking into account the aforementioned uncertainties regarding operationalisation and validity, and in particular the minor number of cases and events.
  • No conclusion can be drawn regarding the extent of the additional benefit.
• Morbidity – Complete Response (CR)
  • The endpoint ‘complete response’ (CR) is an important prognostic factor and relevant to treatment decisions.
  • In study B1371003, the CR endpoint was assessed using the Cheson criteria (2003) through blood and bone marrow examinations.
  • The results for the CR endpoint are classified as having unclear relevance for the present assessment and are presented only as supplementary information.
  • No conclusion can be drawn regarding the extent of the additional benefit.
• morbidity
  • An overall assessment of the results on morbidity does not allow any conclusions to be drawn regarding the extent of the additional benefit.
• quality of life
  • Health-related quality of life was not assessed in study B1371003.
  • No conclusions can be drawn regarding quality of life.
• Side effects – Total adverse events (AEs)
  • AE occurred in almost all patients.
  • The results for the AE endpoint are presented here for the sake of completeness.
• Side effects – severe adverse events (CTCAE grade ≥ 3) and serious SAE (SAE)
  • There were no statistically significant differences between the treatment arms for the endpoints SAE and severe AEs (CTCAE grade ≥ 3).
• Side effects – Discontinuation due to AEs
  • With regard to the endpoint ‘discontinuation due to AEs’, a significant difference was observed in favour of glasdegib + LDAC.
  • Due to the short follow-up period in the control arm – resulting in particular from a high number of deaths – and the many early censorings in the intervention arm, this advantage is subject to uncertainty.
• Side effects – AEs of particular interest
  • For the endpoints ‘AE of particular interest’, there are no statistically significant differences between the treatment arms.
• Side effects
  • An overall review of the results for the ‘side effects’ endpoint category suggests an advantage for glasdegib + LDAC compared with LDAC in terms of the endpoint ‘discontinuation due to AEs’.
• Overall assessment
  • Results are available from the B1371003 study for the benefit assessment of glasdegib in combination with low-dose cytarabine (LDAC) for the treatment of newly diagnosed de novo or secondary acute myeloid leukaemia (AML) in adult patients who are not eligible for standard induction chemotherapy, the B1371003 study provides results for the endpoint categories of mortality, morbidity and side effects.
  • Treatment with glasdegib in combination with LDAC resulted in a statistically significant advantage in overall survival compared with LDAC monotherapy, which is interpreted as a marked prolongation of life.
  • Given the known poor prognosis for patients in this therapeutic indication, which is also reflected in the present study B1371003 by short survival times, the extent of the effect of glasdegib + LDAC on survival time is considered to be considerable.
  • An overall analysis of the morbidity results does not allow any conclusions to be drawn regarding the extent of the additional benefit.
  • Health-related quality of life was not assessed in this study.
  • Conclusions regarding quality of life are of particular importance in this palliative care setting.
  • For the endpoint category of side effects, an advantage can be inferred for glasdegib + LDAC compared with LDAC in terms of the endpoint ‘treatment discontinuation due to AEs’.

Courtesy translation only, please refer to the German original.