Ivosidenib (1) – Tibsovo®

• Clinical trials
  • The AGILE trial is a randomised, multicentre, controlled Phase IIItrial, which has been ongoing since March 2018, in which ivosidenib in combination with azacitidine was compared with placebo in combination with azacitidine in adult patients with newly diagnosed AML harbouring an IDH1 R132 mutation who are unsuitable for standard induction chemotherapy.

Adults with newly diagnosed acute myeloid leukaemia (AML) harbouring an isocitrate dehydrogenase-1 (IDH1) R132 mutation who are unsuitable for standard induction chemotherapy

• Overall, ivosidenib in combination with azacitidine was found to provide significant added benefit for the treatment of adults with newly diagnosed acute myeloid leukaemia (AML) carrying an isocitrate dehydrogenase-1 (IDH1) R132 mutation, which does not provide a major additional benefit for standard induction chemotherapy.
• Overall, the strength of the evidence is classified as an indication.
• mortality
  • Treatment with ivosidenib + azacitidine results in a statistically significant advantage in overall survival compared with placebo + azacitidine.
  • The extent of this advantage is assessed as a major improvement in overall survival, particularly given the known poor prognosis for patients in the therapeutic indication.
• Morbidity – Transfusion independence
  • Transfusion-free status was defined in the pharmaceutical manufacturer’s dossier as the proportion of individuals who had not received any transfusions (of platelets or red blood cells) for at least 24 weeks.
  • Among those with an observation period of at least 24 weeks, no statistically significant differences were observed in the relative risk of receiving a transfusion.
  • The results for the endpoint ‘transfusion independence’ are presented only as supplementary information, taking into account the uncertainties mentioned.
• Morbidity – Symptoms (EORTC QLQ-C30)
  • The time-to-event analyses showed a statistically significant difference in favour of ivosidenib for the endpoint of constipation.
  • For the other endpoints, there was no statistically significant difference between the treatment groups in any case.
  • Overall, no differences relevant to the benefit assessment were identified for ivosidenib in combination with azacitidine with regard to symptoms.
• Morbidity – Health status (EQ-5D VAS)
  • There were no statistically significant differences between the treatment arms with regard to health status.
• morbidity
  • When the results for symptoms and health status are considered together, no difference relevant to the benefit assessment was found between the treatment groups.
• quality of life
  • The time-to-event analyses showed a statistically significant advantage for ivosidenib on the emotional functioning subscale.
  • However, this advantage is not reflected in any other subscale of the EORTC QLQ-C30.
  • Overall, no difference relevant to the benefit assessment was identified in the quality of life endpoint category.
• Side effects – serious AEs (SAEs), severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs
  • There are no statistically significant differences between the treatment arms for SAE, severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs.
• Side effects – Specific AEs
  • In detail, the results for SAE and severe AEs (CTCAE grade ≥ 3) at the system organ class level, which occurred in > 5 % of patients in at least one study arm, show statistically significant effects in favour of ivosidenib in combination with azacitidine for ‘infections and parasitic diseases’ (SAE) and ‘Metabolic and nutritional disorders’ (severe AEs), including the PT ‘Decreased appetite’, there were statistically significant effects in favour of ivosidenib in combination with azacitidine.
  • Furthermore, statistically significant effects in favour of ivosidenib in combination with azacitidine were observed for the PTs ‘asthenia’ and ‘hypotension’ (severe AEs).
  • Among the results for adverse events (AEs) at the System Organ Class (SOC) and Preferred Term (PT) levels, which occurred with an incidence of > 10%, statistically significant effects in favour of ivosidenib in combination with azacitidine were observed (infections and infectious diseases, general administration site disorders (including PT asthenia and PT peripheral oedema), metabolic and nutritional disorders (including PT decreased appetite and PT hypokalaemia), renal and urinary tract disorders, as well as PT constipation and PT cough.
  • Statistically significant effects to the detriment of ivosidenib in combination with azacitidine were observed only for the PTs ‘electrocardiogram: QT prolongation’ and haematomas.
  • Taking an overall view of the results regarding adverse events, no relevant advantage or disadvantage for the benefit assessment can be deduced from this.
• Side effects
  • Overall, with regard to the ‘side effects’ endpoint category, there are no differences relevant to the benefit assessment for ivosidenib in combination with azacitidine.
  • In detail, there are predominantly advantages in individual specific AEs.
• Overall assessment
  • For the endpoint of overall survival, there is a statistically significant advantage in favour of ivosidenib in combination with azacitidine.
  • The extent of this advantage is assessed as a major improvement in overall survival, particularly given the known poor prognosis for patients in the therapeutic indication.
  • With regard to symptoms (assessed using the EORTC QLQ-C30) and health status (assessed using the EQ5D-VAS), no difference relevant to the benefit assessment was found overall between the treatment groups.
  • Nor was any difference relevant to the benefit assessment identified overall with regard to the quality of life endpoint category.
  • Based on the results regarding side effects, ivosidenib in combination with azacitidine showed neither positive nor negative effects on the endpoints of SAE, severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs.
  • In detail, there are predominantly advantages observed for individual specific adverse events.
  • Overall, a substantial added benefit was identified for ivosidenib in combination with azacitidine in the treatment of adults with newly diagnosed acute myeloid leukaemia (AML) harbouring an isocitrate dehydrogenase-1 (IDH1) R132 mutation who are not suitable for standard induction chemotherapy and who do not provide a major additional benefit.

Courtesy translation only, please refer to the German original.