Gilteritinib (1) – Xospata®

Adult patients with relapsed or refractory acute myeloid leukaemia (AML) with an FLT3 mutation

• In conclusion, the G-BA finds that, in the treatment of patients with relapsed or refractory AML with an FLT3 mutation, there is a hint of considerable additional benefit for gilteritinib compared with salvage chemotherapy.
• mortality
  • Overall survival was defined in the ADMIRAL trial as the time from randomisation to death from any cause.
  • Treatment with gilteritinib resulted in a statistically significant advantage in overall survival compared with salvage chemotherapy (hazard ratio (HR) = 0.64; 95% CI [0.49; 0.83], p-value = 0.0007).
  • The median survival time for gilteritinib was 9.3 [7.7; 10.7] months, compared with 5.6 [4.7; 7.3] months, resulting in a 3.7-month prolongation of median overall survival.
  • The sensitivity analyses carried out confirm this result. In particular, both the stratified analysis with censoring for HSZT and the unstratified analysis with censoring for follow-up therapy showed a statistically significant advantage of gilteritinib compared with salvage chemotherapy.
  • Given the known poor prognosis for patients in this therapeutic indication, which is also reflected in the ADMIRAL study by short survival times, the extent of gilteritinib’s effect on survival is regarded as a considerable improvement.
• Morbidity – Remission
  • The endpoint of complete remission (CR) is an important prognostic factor and is relevant to treatment decisions.
  • In the ADMIRAL study, the CR endpoint was assessed using the Cheson criteria through blood and bone marrow examinations.
  • Furthermore, the data submitted by the pharmaceutical manufacturer are classified as invalid, as a significant bias must be assumed due to missing values, particularly in the control arm.
  • The results for the remission endpoint are not taken into account for the present assessment.
• Morbidity – rate of haematopoietic stem cell transplants
  • With regard to the rate of haematopoietic stem cell transplants (HSCT), there is a statistically significant advantage in favour of gilteritinib.
  • 25.5% of patients in the gilteritinib arm and 15.3% of patients in the salvage chemotherapy arm underwent an HSCT.
  • Conclusions regarding patient-relevant therapeutic effects of gilteritinib cannot be drawn from this endpoint, due to a lack of information on the conditions or reasons for or against performing an HSCT, as well as due to differences in how this was implemented across the treatment arms.
  • No conclusion can be drawn regarding the extent of the additional benefit.
• Morbidity – Patient-reported endpoints
  • To record patient-reported endpoints for the assessment of morbidity, the ADMIRAL study utilised the Brief Fatigue Inventory (BFI) questionnaire, items relating to leukaemia-specific symptoms, the Functional Assessment of Chronic Illness Therapy – Dyspnoea Short Form (FACIT-Dys-SF) and the Visual Analogue Scale of the EuroQol 5-Dimensions Questionnaire (EQ-5D-VAS).
  • In the gilteritinib arm, > 70 % of patients completed the questionnaires (with the exception of the FACIT-Dys-SF) at the start of the second and third treatment cycles. In the control group, by contrast, the response rates at the start of the second treatment cycle were only 10–13 per cent.
  • Due to the very high proportion of missing data and the significant difference between the two study arms, the results for these endpoints are invalid and cannot be used for the benefit assessment.
  • On this basis, no conclusion can be drawn regarding the extent of the additional benefit for the patient-reported endpoints used to assess morbidity.
• quality of life
  • To assess quality of life, the Functional Assessment of Cancer Therapy – Leukaemia (FACT-Leu) was used in the ADMIRAL study.
  • As with the patient-reported morbidity endpoints, the response rate for the FACT-Leu in the control group was so minor and the difference between the two treatment arms so great that no valid results can be derived from them.
  • Consequently, no conclusions can be drawn regarding the extent of the additional benefit in terms of quality of life.
• Side effects – Adverse events (AEs)
  • Adverse events (AEs) occurred in almost all patients.
  • The results for the AE endpoint are therefore presented only as supplementary information.
• Overall assessment
  • For the benefit assessment of gilteritinib as monotherapy for the treatment of adult patients with relapsed or refractory AML with an FLT3 mutation, results from the ADMIRAL study are available for the endpoint categories of mortality, morbidity, quality of life and side effects.
  • Treatment with gilteritinib resulted in a statistically significant advantage in overall survival compared with salvage chemotherapy, which is interpreted as a moderate prolongation of survival.
  • Given the known poor prognosis for patients in this therapeutic indication—which is also reflected in the ADMIRAL study by short survival times—the extent of gilteritinib’s effect on survival is regarded as a considerable improvement.
  • It is not possible to assess the impact of gilteritinib on patient-reported morbidity endpoints due to the high proportion of missing data, particularly in the salvage chemotherapy arm, and the associated large differences between the treatment arms.
  • As with the patient-reported morbidity endpoints, no valid data are available for health-related quality of life due to the high proportion of missing data, particularly in the salvage chemotherapy arm, and the associated large differences between the treatment arms.
  • With regard to side effects, due to the short observation period in the comparison arm, comparative conclusions for the first 2 months of treatment can only be drawn on the basis of time-to-event analyses.
  • Furthermore, the high number of censored cases complicates the interpretation of the results.
  • No comparative conclusions regarding side effects occurring in the longer term can be drawn from the data.
  • In the overall assessment of the ‘side effects’ endpoint category, therefore, no advantages or disadvantages for gilteritinib can be identified.

Courtesy translation only, please refer to the German original.