Vorasidenib (1) – Voranigo®

• Clinical trials
  • The INDIGO trial is a multicentre, double-blind, randomised Phase III trial comparing vorasidenib with placebo.

Adults and adolescents aged 12 years and over, weighing at least 40 kg, with predominantly non-contrast-enhancing Grade 2 astrocytomas or oligodendrogliomas with an IDH1-R132or IDH2-R172 mutation, who have undergone surgical intervention only and do not require immediate radiotherapy or chemotherapy

• Hint for a non-quantifiable additional benefit, as the scientific evidence does not permit quantification.
• The level of certainty regarding the established additional benefit is classified as ‘hint’.
• mortality
  • Overall survival was defined in the INDIGO study as the time from randomisation to death, regardless of the underlying cause of death.
  • There was only one death in the vorasidenib arm, meaning that there is no difference relevant to the benefit assessment for this endpoint.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival is defined in the study as the time between randomisation and radiologically confirmed disease progression or death (regardless of the underlying cause), based on assessment by a blinded, independent review committee (BIRC) in accordance with the modified Response Assessment for Neuro-Oncology for Low-Grade Gliomas (RANO-LGG).
  • For the PFS endpoint, there is a statistically significant difference in favour of vorasidenib compared with placebo.
  • The PFS endpoint in question is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint.
  • The overall conclusion regarding the extent of the additional benefit remains unaffected by this.
• Morbidity – Symptoms (PGI-S and PGI-F)
  • The Patient Global Impression of Severity (PGI-S) and Patient Global Impression of Frequency (PGI-F) assess the perceived severity of symptoms (glioma symptoms, neurocognitive functions and epileptic seizures) and the perceived frequency of epileptic seizures, respectively.
  • With regard to the severity of glioma symptoms and neurocognitive function, it is unclear exactly which symptoms are recorded by patients in the PGI-S questionnaire.
  • The operationalisation of the PGI-S and PGI-F in relation to epileptic seizures is considered adequate.
  • The questionnaires were supplemented in the INDIGO study with the second protocol amendment (version 3.0; 17 December 2020) and were therefore not administered to all enrolled patients from the start of the study.
  • At baseline, data are available for only 14% (vorasidenib arm) and 10% (control arm) of the study population, respectively.
  • At the end of treatment, the response rates for the FAS population were 10% in the vorasidenib arm and 24% in the control arm.
  • Consequently, the data from the PGI-S and PGI-F assessment tools cannot be evaluated as a whole.
• Morbidity – Health status (EQ-5D VAS)
  • Health status is assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • In the dossier, the pharmaceutical manufacturer has submitted responder analyses, operationalised as the time to the first deterioration of ≥ 15 % (corresponding to ≥ 15 points).
  • No statistically significant differences were observed between the treatment arms.
• Quality of life – Functional Assessment of Cancer Therapy – Brain (FACT-Br)
  • Health-related quality of life among patients in the INDIGO study is assessed using the FACT-Br questionnaire, which comprises the FACT-G and a subscale for primary brain tumours (FACT-BrS).
  • In the dossier, the pharmaceutical manufacturer presents responder analyses defined as the time to the first deterioration of ≥ 15 % of the scale range.
  • No statistically significant differences were observed between the treatment arms.
• Side effects – Total adverse events (AEs)
  • In the INDIGO study, an AE occurred in almost all patients in the vorasidenib arm and in 95.1% of patients in the placebo arm.
  • The results are presented here for supplementary information only.
• Overall assessment
  • For the benefit assessment of vorasidenib for the treatment of predominantly non-contrast-enhancing Grade 2 astrocytomas or oligodendrogliomas with an IDH1-R132mutation or an IDH2-R172 mutation in adult and adolescent patients aged 12 years and over and weighing at least 40 kg, who have undergone surgical intervention only and do not require immediate radiotherapy or chemotherapy, results on mortality, morbidity, quality of life and side effects from the double-blind RCT INDIGO, in which vorasidenib was compared with placebo.
  • No difference relevant to the benefit assessment was observed for the overall survival endpoint.
  • Morbidity was assessed using the endpoints of epileptic seizures, symptoms (PGI-S; PGI-F) and health status (EQ-5D VAS).
  • There is an advantage of vorasidenib for the endpoint ‘epileptic seizures’.
  • No evaluable data are available regarding symptoms (as measured by PGI-S and PGI-F).
  • With regard to health status (EQ-5D VAS), there is no statistically significant difference between the treatment arms.
  • For health-related quality of life, assessed using the FACT-Br, there are no statistically significant differences between the treatment arms.
  • With regard to side effects, the overall rate of serious AEs (SAEs) shows no difference between the treatment arms that is relevant for the benefit assessment.
  • Treatment with vorasidenib was associated with a disadvantage in terms of severe AEs.
  • No data are available for the endpoint of therapy discontinuation due to AEs.
  • Overall, there is an advantage in the morbidity endpoint category for the endpoint ‘epileptic seizures’.
  • Due to the aforementioned uncertainties, the extent of the improvement in epileptic seizures cannot be reliably quantified.
  • Furthermore, there is a disadvantage in terms of side effects for the overall rate of severe AEs; however, this does not, on the whole, call the additional benefit into question.

Courtesy translation only, please refer to the German original.