Selumetinib (1) – Koselugo®

• Clinical trials
  • The SPRINT trial is an ongoing, open-label, single-arm, multicentre 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.
• Consequently, with regard to the validity of the evidence, there is a hint of additional benefit.
• mortality
  • In Phase II of the SPRINT study, no deaths were observed up to the data cut-off date of 29 March 2019.
  • No conclusion can be drawn regarding the extent of the additional benefit, as there is no control group.
• Morbidity – Progression-free survival (PFS)
  • PFS was assessed as a secondary endpoint in the SPRINT study and defined as the time from the first cycle of study treatment to progression or death from any cause, regardless of whether participants discontinued the study treatment or received another pancreatic cancer treatment (following discontinuation of the study treatment) prior to progression.
  • Notwithstanding this, no conclusions can be drawn from the results of the SPRINT study regarding the extent of the additional benefit for the PFS endpoint, as there is no control group.
• Morbidity – Change in tumour volume
  • In the SPRINT trial, a reduction in the target lesion (best achieved percentage volume reduction) of –25% was demonstrated.
  • Approximately 96% of patients experienced a reduction in tumour volume during the course of the study whilst being treated with selumetinib.
  • However, given the clinical presentation and stage of the disease, it can be assumed with reasonable certainty that no spontaneous remissions occur during the natural course of the disease.
  • 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.
• Morbidity – Objective Response Rate (ORR)
  • The objective response rate was assessed as the primary endpoint in the SPRINT study and defined as the percentage of Phase II patients who achieved a confirmed complete or partial response (a reduction in the volume of the target PN of 20% or more).
  • In accordance with the operationalisation, the objective response rate endpoint was assessed using imaging procedures rather than on the basis of symptoms.
  • This endpoint is not used for the benefit assessment, as the change in tumour volume was already considered as an endpoint; however, it is presented here for supplementary information.
• Morbidity – Global assessment of clinical change
  • The global assessment of clinical change was recorded using the Global Impression of Change (GIC).
  • In the SPRINT study, improvements over time were observed compared with the time before the start of treatment in the Global Impression of Change (GIC) assessment of clinical change for patients aged 3 to 18 years.
• Morbidity – Pain
  • Improvements over time compared with baseline were observed for the endpoint ‘worst pain’ in patients aged 8 years and over.
  • The ‘pain’ endpoint was not assessed in children under 8 years of age.
• Morbidity – Visual acuity (HOTV test)
  • In the analysis of visual acuity, only 5 patients in total could be included for the eye affected by PN.
  • Compared with baseline, no improvements were observed, and a deterioration was noted for the eye affected by PN.
  • However, the certainty and interpretability of the results are very limited due to the open-label study design without a control group and the small sample size; therefore, no conclusions can be drawn regarding the additional benefit of selumetinib.
• Morbidity – Motor function (Grooved Pegboard Test)
  • With regard to the Grooved Pegboard Test, mild to moderate improvements were observed over time.
  • However, due to the single-arm study design, it is not possible to distinguish whether these improvements are due to treatment with selumetinib or, for example, to practice effects.
  • For the reasons stated, there are significant uncertainties in the interpretation of the results for this endpoint, which is why it is not used in this assessment to quantify the extent of the additional benefit.
• Morbidity – Patient-Reported Outcomes Measurement Information System (PROMIS)
  • For the PROMIS ‘Mobility’ and ‘Upper Limb’ scales, slight improvements from baseline were observed in patients aged 8 to 18 years at the study visit prior to cycle 13.
• Quality of life – Paediatric Quality of Life Inventory (PedsQL)
  • The results of Phase II of the SPRINT study show an improvement in health-related quality of life over the course of the study compared with baseline for children under 8 years of age and for those aged 8 years and over.
• Side effects – Total adverse events (AEs)
  • Almost all patients enrolled in the study experienced an adverse event.
• Overall assessment
  • For the endpoint ‘change in tumour volume’, a significant reduction in tumour volume was observed compared with the baseline value at the start of the study.
  • Given the specific characteristics of the disease in this therapeutic indication – which include, amongst other things, externally visible tumours as well as tumour-related disfigurement and functional impairments, regardless of the visibility of the tumours – the reduction in tumour volume is, in principle, an important therapeutic objective.
  • Against this background, despite remaining uncertainties regarding the operationalisation of the endpoints and an 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.
  • However, in the present assessment, no valid conclusions can be drawn due to the lack of a control group.
  • 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.