Selumetinib (4) – Koselugo®

• Clinical trials
  • The KOMET trial is an ongoing, multicentre, randomised, double-blind Phase III trial comparing selumetinib (+ best supportive care, BSC) with placebo (+ BSC).

Adults with symptomatic, inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1)

• Overall, selumetinib shows advantages in the endpoints ‘chronic pain’, ‘pain spikes’ and reduction in tumour volume, and a disadvantage in terms of severe AEs. Overall, even taking into account the lack of suitable data on health-related quality of life and physical functioning, selumetinib + BSC provides a minor additional benefit compared with placebo + BSC in adults for the treatment of symptomatic, inoperable PN in NF1.
• The certainty of evidence for the observed additional benefit is classified as an indication.
• mortality
  • Overall mortality
  • No deaths occurred in either treatment arm, meaning that there is no difference relevant to the benefit assessment for this endpoint.
• Morbidity – Chronic pain assessed using the Numerical Rating Scale (NRS), Patient Global Impression of Severity (PGIS) and Patient Global Impression of Change 1 (PGIC-1) / 2 (PGIC-2)
  • The endpoint ‘chronic pain’ was assessed daily using the NRS. A statistically significant advantage was observed in favour of selumetinib compared with placebo.
  • The ‘chronic pain’ endpoint was assessed using the PGIS, PGIC-1 and PGIC-2. The PGIC-1 and PGIS were each recorded at clinic visits at the end of cycles 1, 2, 4, 6, 8, 10 and 12, whilst the PGIC-2 was collected at the end of cycle 12. For the PGIS, PGIC-1 and PGIC-2, a statistically significant improvement was also observed for selumetinib compared with placebo.
  • With regard to the available results for the PGIS, PGIC-1 and PGIC-2, there are differences in the way the ‘chronic pain’ endpoint is assessed. Overall, the results for the PGIS, PGIC-1 and PGIC-2 are interpreted as confirming the findings of the NRS.
• Morbidity – pain peaks assessed using the Numerical Rating Scale (NRS), Patient Global Impression of Severity (PGIS) and Patient Global Impression of Change 1 (PGIC-1) / 2 (PGIC-2)
  • The endpoint ‘pain peaks’ was assessed daily using the NRS. A statistically significant advantage was observed in favour of selumetinib compared with placebo.
  • The ‘pain peaks’ endpoint was assessed using the PGIS, PGIC-1 and PGIC-2. The PGIC-1 and PGIS were recorded at clinic visits at the end of cycles 1, 2, 4, 6, 8, 10 and 12, whilst the PGIC-2 was collected at the end of cycle 12. For the PGIS, PGIC-1 and PGIC-2, a statistically significant improvement was also observed for selumetinib compared with placebo.
  • With regard to the available results for the PGIS, PGIC-1 and PGIC-2, there is also – as with the ‘chronic pain’ endpoint – a difference in how the ‘pain peaks’ endpoint is measured. Overall, the results for the PGIS, PGIC-1 and PGIC-2 are interpreted as confirming the results of the NRS.
• quality of life
  • In its dossier, the pharmaceutical manufacturer presents analyses of the PlexiQoL and classifies these as relating to health-related quality of life. The PlexiQoL assesses exclusively social and psychological aspects in patients with plexiform neurofibromas associated with neurofibromatosis type 1. Physical aspects, on the other hand, are not assessed. The PlexiQoL results are therefore assigned to the morbidity endpoint category (psychosocial morbidity). Overall, therefore, no suitable data are available for the quality of life endpoint category.
• Side effects – Total adverse events (AEs)
  • In the KOMET study, an AE occurred in almost all patients in both the selumetinib and placebo arms. The results are presented here for supplementary information only.
• Overall assessment
  • The benefit assessment of selumetinib in adults for the treatment of symptomatic, inoperable PN in NF1 is based on the results of the KOMET study regarding the endpoint categories of mortality, morbidity and side effects compared with placebo.
  • No deaths occurred in the KOMET study.
  • For the endpoint ‘change in target lesion volume’ (‘best achieved percentage change in target lesion volume’ compared with baseline), selumetinib demonstrated a significant reduction in tumour volume compared with placebo, relative to the baseline value at the start of the study. Given the specific characteristics of the disease – which, in addition to externally visible tumours, may also include tumour-related disfigurement and functional impairments regardless of the tumours’ visibility – a reduction in tumour volume should be regarded as an important therapeutic goal in this context. In view of this, despite remaining uncertainty, an improvement in therapeutic benefit can be observed for treatment with selumetinib in terms of a significant reduction in tumour volume compared with baseline. Advantages in the morbidity endpoint category are also evident for the endpoints ‘chronic pain’ (measured using NRS, PGIS, PGIC-1 and PGIC-2) and ‘pain peaks’ (measured using NRS, PGIS, PGIC-1 and PGIC-2).
  • No suitable data were collected in the KOMET study for the health-related quality of life endpoint category.
  • In the ‘side effects’ endpoint category, selumetinib showed a disadvantage in terms of severe AEs; no statistically significant differences were observed in the endpoints ‘severe AEs’ and ‘therapy discontinuations due to AEs’.
  • Overall, selumetinib shows advantages in the endpoints ‘chronic pain’, ‘pain spikes’ and reduction in tumour volume, and a disadvantage in terms of severe AEs. Overall, even taking into account the lack of suitable data on health-related quality of life and physical functioning, selumetinib + BSC shows a minor additional benefit compared with placebo + BSC in adults for the treatment of symptomatic, inoperable PN in NF1.

Courtesy translation only, please refer to the German original.