Selumetinib (2) – Koselugo®

• Clinical trials
  • The SPRINT trial is an ongoing, multicentre, open-label, single-arm Phase I/II trial.

Children aged 3 years and over and adolescents with symptomatic, inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1)

• Hint for a non-quantifiable additional benefit, as the scientific data do not permit quantification.
• The level of certainty is classified as ‘hint’.
• mortality
  • In Phase II of the SPRINT trial, no deaths were observed up to the data cut-off date of 31 March 2021.
  • No conclusion can be drawn regarding the extent of the additional benefit, as there is no control group.
• Morbidity – Progression-free survival (PFS)
  • In the SPRINT study, PFS was assessed as a secondary endpoint.
  • PFS was defined as the time from the 1st cycle of study treatment until the MRI assessment in which progression was detected, or until death from any cause, regardless of whether patients discontinued the study treatment or received another PN treatment (following discontinuation of the study treatment) prior to progression.
  • Nevertheless, no conclusions regarding the extent of the additional benefit can be drawn from the results of the SPRINT study for the PFS endpoint, as there is no control group.
  • The PFS endpoint is presented for supplementary information.
• Morbidity – Change in tumour volume
  • The endpoint ‘change in tumour volume’ was assessed as a secondary endpoint in the SPRINT study.
  • The endpoint was operationalised as the change in volume of the PN defined as the target lesion, measured using volumetric 3D MRI.
  • The endpoint ‘change in tumour volume’ is considered a patient-relevant endpoint, as this indication represents a special case.
  • In the SPRINT study, a reduction in the target lesion (best achieved percentage volume reduction) of –27% was demonstrated.
  • A reduction in volume was observed in 96% of patients.
  • Given the absence of a control group, the fundamental question initially arises as to the extent to which this represents a treatment effect.
  • However, according to the clinical experts at the oral hearing, given the clinical presentation and stage of the disease in question, it can be assumed that no spontaneous remissions occur during the natural course of the disease.
  • Nevertheless, a reduction in tumour volume in this therapeutic indication should, in principle, be regarded as a therapeutic goal.
  • Against this background, despite remaining uncertainties, an improvement in the therapeutic benefit of treatment with selumetinib can be established in terms of a relevant reduction in tumour volume.
• Morbidity – Objective Response Rate (ORR)
  • The objective response rate was assessed as the primary endpoint in the SPRINT study.
  • The ORR was defined as the percentage of patients in stratum 1 of the Phase II trial who achieved a confirmed complete or partial response (a reduction in the volume of the target PN of 20% or more).
  • The objective response rate endpoint was not assessed on the basis of symptoms, but rather using imaging procedures.
  • For this reason, the objective response rate is assessed in the present operationalisation as not directly relevant to patients.
  • This endpoint is not used for the benefit assessment, as the change in tumour volume has already been taken into account as an endpoint.
  • However, the endpoint is presented for supplementary information.
• Morbidity – Global assessment of clinical change
  • The global assessment of clinical change was recorded using the Global Impression of Change (GIC), a single-item scale for assessing the clinical significance of changes in pain intensity or other symptoms.
  • In the SPRINT trial, a modified 3-item version of the GIC was used.
  • The change in tumour pain, overall pain and PN-related morbidity was measured compared with the time before taking the study medication.
  • In the SPRINT study, improvements over time were observed in the Global Impression of Change (GIC) score—as reported by patients aged 3 to 18 years—compared with the time before the start of treatment.
• Summary assessment of the endpoints for the investigation of symptoms, physical functioning or functional limitations, and health-related quality of life
  • Patients with plexiform neurofibromas show individual differences in terms of symptoms and physical functioning or functional limitations.
  • However, in the present assessment, the absence of a control group means that no valid interpretation or evaluation of the results for these endpoints can be made.
  • Consequently, no conclusion regarding additional benefit can be drawn on the basis of these endpoints.
• Side effects – Total adverse events (AEs)
  • An adverse event occurred in almost all children and adolescents (49 patients (99 %)).
  • These are presented here for supplementary information only.
• Overall assessment
  • Results from the uncontrolled clinical study SPRINT are available for the post-authorisation benefit assessment of selumetinib for the treatment of plexiform neurofibromas in children aged 3 years and older and adolescents with neurofibromatosis type 1.
  • Due to the single-arm study design, no comparative assessment is possible for the endpoints relating to mortality, morbidity, quality of life and side effects.
  • For the endpoint ‘change in tumour volume’, a significant reduction in tumour volume is observed compared with the baseline value at the start of the study.
  • In view of this, despite remaining uncertainties regarding the operationalisation of the endpoints and the overall limited interpretability of the results, an improvement in the therapeutic benefit of treatment with selumetinib can be observed in terms of a significant reduction in tumour volume.
  • The study also assessed several endpoints relating to symptoms and physical functioning or functional limitations.
  • However, due to the absence of a control group, no valid conclusions can be drawn.
  • Overall, a non-quantifiable additional benefit is identified for selumetinib in the treatment of symptomatic, inoperable, plexiform neurofibromas in children aged 3 years and older and adolescents with neurofibromatosis type 1, as the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.