Ivosidenib (2) – Tibsovo®

• Clinical trials
  • The pharmaceutical manufacturer submitted data from the pivotal, randomised, double-blind, placebo-controlled Phase III ClarIDHy trial for the benefit assessment.
  • In this trial, ivosidenib was compared with placebo, with additional supportive measures in the form of best supportive care (BSC) permitted in both treatment arms.

Adults with locally advanced or metastatic cholangiocarcinoma harbouring an IDH1 R132 mutation who have previously received at least one systemic therapy

• The strength of the evidence is classified as ‘hint’.
• mortality
  • In the ClarIDHy study, overall survival was defined as the time from randomisation to death from any cause.
  • No statistically significant difference was observed between the treatment arms for the endpoint of overall survival.
  • The analyses of overall survival are based on the ITT population, which also includes patients from the control arm who switched to the intervention arm following disease progression.
  • As of the data cut-off date of 31 May 2020, 43 (70.5%) of the patients had switched from the control arm to treatment with ivosidenib.
  • Overall, the analysis of overall survival using the RPSFT model is not taken into account in this benefit assessment.
  • With regard to the analysis of overall survival based on the ITT population, an effect modification is observed for the characteristic of ECOG status at the start of the study.
  • As this effect modification is not observed for other endpoints in the ClarIDHy study, the statistical significance of this subgroup result is considered insufficient for the assessment of additional benefit overall and is therefore not taken into account.
• Morbidity – Progression-free survival (PFS)
  • PFS was the primary endpoint of the ClarIDHy study and was defined as the time from randomisation to the first confirmed disease progression (according to RECIST criteria version 1.1) or death from any cause, whichever occurred first.
  • PFS was statistically significantly prolonged in the ivosidenib + BSC arm compared with the placebo + BSC arm.
  • The PFS endpoint is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories.
  • The ‘disease progression’ component of morbidity is assessed according to RECIST v1.1 criteria and is therefore not symptom-based but determined using imaging procedures.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint.
  • Data on morbidity and health-related quality of life are potentially relevant for the interpretation of the PFS results, particularly where, as in the present case, radiologically determined disease progression is associated with effects on morbidity and/or quality of life.
  • However, no suitable data on morbidity and health-related quality of life are available from the ClarIDHy study.
  • Consequently, it is not possible to assess the extent to which the advantage in PFS observed in the ClarIDHy study using imaging procedures is associated with an advantage in terms of morbidity and/or health-related quality of life.
  • The results for the PFS endpoint are therefore not taken into account in this assessment.
• Morbidity – Symptoms (EORTC QLQ-C30 and EORTC QLQ-BIL21)
  • Data on patient-reported symptoms were collected in the ClarIDHy study using the EORTC QLQ-C30 and EORTC QLQ-BIL21 assessment tools.
  • However, the response rates are below 70 per cent, meaning that the validity of the results cannot be considered reliable.
  • The data are therefore unusable and do not allow any conclusions to be drawn regarding the extent of the additional benefit.
• Morbidity – Health status
  • The health status reported by patients was assessed using the visual analogue scale (VAS) of the EQ-5D.
  • However, the response rates here are also below 70 per cent, meaning that the data are considered unusable and do not allow any conclusions to be drawn regarding the extent of the additional benefit.
• Quality of life – functional scales (EORTC QLQ-C30 and EORTC QLQ-BIL21)
  • In line with the above comments on symptoms (EORTC QLQ-C30 and EORTC QLQ-BIL21), no usable data are available on health-related quality of life either, due to response rates below 70%, which would allow conclusions to be drawn regarding the extent of the additional benefit.
• Side effects – Total adverse events (AEs)
  • Total adverse events (AEs)
  • AEs occurred in almost all patients in the ClarIDHy study.
  • The results are presented here for supplementary information only.
• Side effects – serious AEs (SAEs), severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs
  • Serious AEs (SAEs), severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs
  • No statistically significant differences were observed between the treatment arms for the endpoints of serious AEs (SAEs), severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs.
• Conclusion on side effects
  • Overall, with regard to the endpoint category of side effects, there are no differences relevant to the benefit assessment for ivosidenib + BSC.
  • In detail, there are advantages in relation to specific AEs.
• Overall assessment
  • The results of the ClarIDHy study are available for the benefit assessment of ivosidenib as monotherapy for the treatment of adults with locally advanced or metastatic cholangiocarcinoma harbouring an IDH1 R132 mutation who have previously received at least one systemic therapy.
  • In the study, which was completed in 2021, ivosidenib + BSC was compared with placebo + BSC.
  • No statistically significant difference in overall survival was observed between the treatment arms.
  • In the morbidity endpoint category, due to insufficient response rates, no usable data are available for patient-reported symptoms and health status that would allow conclusions to be drawn regarding the extent of the additional benefit.
  • Similarly, with regard to health-related quality of life, there are no usable data available due to insufficient response rates that would allow conclusions to be drawn regarding the extent of the additional benefit.
  • Based on the results regarding side effects, there are neither positive nor negative effects for ivosidenib + BSC in the endpoints of SAE, severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs.
  • In detail, advantages are evident for individual specific adverse events.

Courtesy translation only, please refer to the German original.