Mirdametinib (1) – Ezmekly®

• Clinical trials
  • The ReNeu trial is an ongoing, multicentre, open-label, single-arm Phase IIb trial.

Adults and children aged 2 years and over with symptomatic, inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1)

• Extent of the additional benefit and strength of the evidence for mirdametinib:
• Hint for a non-quantifiable additional benefit, as the scientific data do not permit quantification.
• The certainty of the evidence is classified as ‘hint’.
• mortality
  • Deaths
  • For the endpoint ‘deaths’, only deaths for which a link to a preceding AE was identified were recorded. Deaths due to progression of the underlying disease, as well as deaths without a recognisable preceding AE as defined in the study, were not included in the endpoint. The data are therefore not assessable.
• Morbidity – Progression-free survival (PFS)
  • In the ReNeu study, PFS was defined as the time from the first cycle of study treatment until the MRI assessment in which progression was detected, or until death, whichever occurred first. Progression was defined as an increase of at least 20% in the volume of the target lesion according to REiNS criteria, as measured by volumetric MRI scans.
  • Nevertheless, no conclusions can be drawn from the results of the ReNeu study regarding the extent of the additional benefit for the PFS endpoint, as there was no control group. The PFS endpoint is presented for supplementary information.
• Quality of life – Paediatric Quality of Life Inventory (PedsQL)
  • The patient-reported assessment of quality of life using the PedsQL is considered to be relevant to patients.
  • At the predefined primary analysis time point (cycle 13) and in subsequent cycles, the response rate in the paediatric and adolescent cohort was over 70 per cent, but below 70 per cent in the adult cohort. Due to the low response rate among adults, the data for the Pediatric Quality of Life Inventory (PedsQL) endpoint cannot therefore be evaluated as a whole, regardless of the fact that a comparative assessment of the endpoint is not possible due to the single-arm study design.
• Side effects – Total adverse events (AEs)
  • Adverse events occurred in all participating patients. These are presented here for supplementary information only.
• Overall assessment
  • Results from the uncontrolled clinical study ReNeu are available for the benefit assessment of mirdametinib for the treatment of symptomatic, inoperable plexiform neurofibromas in children aged 2 years and over, adolescents and adults with neurofibromatosis type 1. Data on mortality, morbidity, quality of life and side effects were collected. Due to the single-arm study design, no comparative assessment is possible.
  • For the endpoint of mortality, only deaths for which a link to a preceding AE was identified were recorded. The data are therefore not evaluable.
  • 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 – 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 uncertainties regarding the operationalisation of the endpoints and an overall limited interpretability of the results, an improvement in the therapeutic benefit of treatment with mirdametinib can be observed in terms of a significant reduction in tumour volume compared with baseline.
  • In the study, the 6-minute walk test (6MWT) endpoint was also assessed in a patient population to evaluate physical functioning or functional impairment. Consequently, the results for the 6MWT do not reflect the physical performance of the entire study population. Furthermore, results for this patient population are, in turn, only available for a patient population of this patient population. Overall, the data are therefore deemed unevaluable and are presented only as supplementary information.
  • Health-related quality of life was assessed using a suitable measurement tool (PedsQL); however, due to a low response rate among adult patients, the results were not used for the benefit assessment.
  • With regard to side effects, treatment with mirdametinib was associated with some severe (CTCAE grade ≥ 3) and serious adverse events, as well as therapy discontinuations due to adverse events. As there is no comparison with a control group, no valid conclusions can be drawn.

Courtesy translation only, please refer to the German original.