Selumetinib (5) – Koselugo®

• Clinical trials
  • The SPRINKLE trial is a single-arm, open-label Phase I/II trial investigating selumetinib in granule form in children aged 1 year and over but under 7 years with PN associated with NF1.
  • The SPRINT trial is a single-arm, open-label Phase I/II trial investigating selumetinib in capsule form in children aged 3 years and over and adolescents with PN associated with NF1.
  • The KOMET trial is a randomised, controlled, double-blind Phase III trial investigating selumetinib capsules in adults with PN associated with NF1 compared with placebo.

Children aged between 1 year and under 3 years with symptomatic, inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1)

• Hint for a non-quantifiable additional benefit.
• Based on the statements of the clinical experts, it can be assumed that, given the present clinical picture and stage of the disease, no spontaneous remissions occur during the natural course of the disease.
• Furthermore, the rate of tumour growth is significantly higher, particularly in early childhood, than in older patients.
• Due to the single-arm study design of the SPRINKLE trial, a comparative assessment of the data presented is not possible. The data are therefore fundamentally unsuitable for a benefit assessment.
• An exception to this is the morbidity endpoint of volume change in the target lesion.
• In the SPRINKLE trial, a reduction in the target lesion (best achieved percentage change in volume) of –10 % was demonstrated.
• Furthermore, the results are subject to further uncertainties due to the large inter-patient variability and the minor number of study participants.
• No suitable data are available for other patient-relevant endpoints.
• Consequently, it is not possible to weigh this against potential disadvantages in the overall assessment.
• Quantifying the additional benefit is complicated by the wide inter-patient variability, the small number of study participants and the comparison with baseline.
• In contrast, the results of the SPRINKLE study on tumour volume reduction are supported by the consistent findings of the SPRINT study in the directly adjacent patient population of children aged 3 years and over and adolescents.
• Consequently, in the present assessment scenario, a non-quantifiable additional benefit is identified for selumetinib in children aged 1 year to under 3 years for the treatment of symptomatic, inoperable PN in NF1.
• Due to the limitations mentioned, the certainty of the findings is classified as ‘hint’.
• Morbidity – change in volume of the target lesion
  • The target lesion was defined as the most clinically relevant, inoperable PN that could be assessed using volumetric 3D MRI measurement.
  • This endpoint was assessed as a secondary endpoint in the SPRINKLE study and operationalised as the change in volume of the target lesion compared with baseline, measured using volumetric 3D MRI.
  • In the SPRINKLE study, a reduction in the target lesion (best achieved percentage change in volume) of –10% was demonstrated.
  • The volume of the PN represents the relevant severity of the disease and is the cause of any symptoms that may be present, including functional limitations, and may also be associated with disfigurement.
  • Against this background, despite remaining uncertainties, an improvement in the therapeutic benefit of treatment with selumetinib can be observed in terms of a relevant reduction in tumour volume compared with baseline, thereby establishing an advantage for selumetinib at the endpoint of change in tumour volume.
• Overall assessment
  • Given the available data, and despite the single-arm study design, it is possible to infer an additional benefit of selumetinib for the treatment of children aged 1 year to under 3 years with symptomatic, inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1).
  • Based on the statements of the clinical experts, it can be assumed that, given the present clinical picture and stage of the disease, no spontaneous remissions occur during the natural course of the disease.
  • At the endpoints, therefore, despite remaining uncertainties, an improvement in therapeutic benefit can be observed for treatment with selumetinib in terms of a relevant reduction in tumour volume compared with baseline, indicating an advantage for selumetinib in the endpoint of change in tumour volume.

Courtesy translation only, please refer to the German original.