Nirogacestat (1) – Ogsiveo®

• Clinical trials
  • The DeFi trial is a randomised, multicentre, double-blind, controlled Phase III trial in which nirogacestat was compared with placebo.

Adults with progressive desmoid tumours requiring systemic treatment

• Hint for a minor additional benefit
• There is a hint of a minor additional benefit for nirogacestat in the treatment of advanced desmoid tumours requiring systemic treatment.
• mortality
  • For the endpoint of mortality, deaths from any cause were continuously recorded as part of the monitoring of side effects.
  • One death occurred in the placebo arm.
  • There is no significant difference in mortality.
• Morbidity – Progression-free survival
  • Progression-free survival (PFS) was defined in the DeFi study as the time from randomisation to the date of radiological progression or death, whichever occurred first, based on the date of imaging documentation of disease progression in accordance with the RECIST (Response Evaluation Criteria in Solid Tumours, Version 1.1) criteria.
  • With the fifth protocol amendment (9 February 2021), radiological progression was supplemented by clinical progression.
  • The PFS endpoint in question is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the patient relevance of the PFS endpoint.
  • The overall assessment of the extent of the additional benefit remains unaffected by this.
• Morbidity – change in tumour volume (supplementary)
  • The endpoint ‘change in tumour volume’ was pre-specified as a secondary endpoint for the DeFi study and was later changed to an exploratory endpoint.
  • In the DeFi study, a reduction in tumour volume was observed by cycle 7 with nirogacestat compared with placebo.
  • The change in tumour volume alone is not, in itself, clinically relevant to patients.
  • The results for the endpoint ‘change in tumour volume’ are presented for supplementary information only.
• Morbidity – GOunder/DTRF DEsmoid Symptom/Impact Scale (GODDESS-DTSS/-DTIS)
  • The GOunder/DTRF DEsmoid Symptom/Impact Scale (GODDESS) is a disease-specific tool developed to quantify the symptoms of desmoid tumours and their impact on patients.
  • The responder analyses of time to first deterioration for the weighted DTSS total score show a statistically significant advantage for nirogacestat.
  • For the GODDESS-DTIS, the three domain scores ‘Physical Functioning’, ‘Sleep’ and ‘Emotion’ were taken into account.
  • In the time-to-first-deterioration responder analysis, a statistically significant difference was observed between the two treatment arms in favour of nirogacestat for both the ‘Physical Functioning’ and ‘Sleep’ domain scores.
  • In the subgroup analysis, an effect modification was observed for physical functioning with regard to the characteristics ‘tumour location’ and ‘any prior therapy’.
• Morbidity – Brief Pain Inventory Short Form (BPI-SF)
  • Pain was assessed in the DeFi study using the BPI-SF questionnaire.
  • A statistically significant difference in favour of nirogacestat was observed for the “Pain-related impairment” subscale.
• Morbidity – EORTC QLQ-C30
  • Symptoms were assessed using the EORTC QLQ-C30 questionnaire.
  • In the responder analysis, a statistically significant disadvantage for nirogacestat was observed for the symptom scales ‘Nausea and Vomiting’, ‘Loss of Appetite’ and ‘Diarrhoea’.
  • For the ‘constipation’ symptom scale, a statistically significant advantage was observed for nirogacestat.
• Quality of life – EORTC QLQ-C30
  • Health-related quality of life was assessed using the EORTC QLQ-C30 questionnaire.
  • In the responder analysis, a statistically significant difference was observed for the ‘Physical Functioning’ subscale, with an advantage for nirogacestat.
  • Overall, treatment with nirogacestat appears to offer an advantage in terms of health-related quality of life.
• Side effects – Total adverse events (AEs)
  • In the DeFi study, an AE occurred in almost all patients in the control arm and in all patients in the intervention arm.
  • The results are presented here for supplementary information only.
• Overall assessment
  • For the benefit assessment of nirogacestat in the treatment of advanced desmoid tumours requiring systemic treatment, results on mortality, morbidity, quality of life and side effects from the double-blind RCT DeFi, in which nirogacestat was compared with placebo.
  • No significant difference was observed in mortality.
  • Morbidity was assessed using the GODDESS-DTSS, GODDESS-DTIS, BPI-SF, PGIC, PGIS and EORTC QLQ-C30. Advantages were observed for the majority of the morbidity endpoints assessed. It should be noted, however, that some symptoms were recorded twice across several assessment tools. The disadvantages evident from the symptom scales are also apparent in the analyses of safety endpoints and may therefore reflect side effects of nirogacestat. In view of the positive effects, some of which are significant, an advantage of treatment with nirogacestat in terms of morbidity can be identified, the extent of which is assessed overall as a significant improvement.
  • Treatment with nirogacestat demonstrates an advantage in physical functioning in terms of health-related quality of life.
  • With regard to side effects, severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs occurred during treatment with Nirogacestat. Specifically, disadvantages were observed for the endpoints ‘gastrointestinal disorders’ and ‘diarrhoea’. When the endpoints relating to side effects are considered as a whole, a disadvantage is observed.
  • In the overall assessment of the available results for patient-relevant endpoints, there are, in some cases, clear advantages in the endpoint category of morbidity, as well as an advantage in health-related quality of life. Conversely, there are disadvantages with regard to side effects. In a decision weighing up the extent of the additional benefit, the G-BA concludes that Nirogacestat offers a minor additional benefit compared with placebo for the treatment of advanced desmoid tumours requiring systemic treatment.

Courtesy translation only, please refer to the German original.