Trametinib (Spexotras, 1) – Spexotras®

• Clinical trials
  • The G2201 trial is a multicentre, open-label Phase II trial comprising two cohorts, designed to investigate the efficacy and safety of trametinib in combination with dabrafenib in children and adolescents aged ≥ 12 months to < 18 years with low-grade ( LGG cohort) and high-grade (HGG cohort) gliomas and a BRAF V600E mutation.
  • Study X2101 is an open-label, single-arm trial comprising four parts, designed to investigate trametinib in combination with dabrafenib in children and adolescents with recurrent or refractory solid tumours following at least one prior line of treatment; parts C and D are used for the benefit assessment, as only these largely comprise a combination of trametinib and dabrafenib that is essentially in line with the summary of product characteristics (SmPC).

a1) Paediatric patients aged 1 year and over with a low-grade glioma (LGG) harbouring a BRAF V600E mutation who require systemic therapy – patients without prior treatment for LGG

• Hint of considerable additional benefit.
• Overall, the G-BA concludes that, due to the clear advantages in terms of side effects, trametinib in combination with dabrafenib offers considerable additional benefit for paediatric patients with LGG who have not previously been treated.
• The certainty of the evidence regarding the extent of the additional benefit identified is classified as ‘hint’.
• mortality
  • In the G2201 study, overall survival was defined as the period from the start of treatment until death, regardless of the underlying cause of death.
  • For paediatric patients with untreated LGG, there is no statistically significant difference based on the results of the G2201 study.
• Morbidity – Overall Response Rate
  • The overall response rate (ORR) was the primary endpoint in the G2201 study. Response was assessed according to the RANO criteria by a central, independent review committee and by the trial staff.
  • When considering the results for the overall response rate, 52.1% of patients in the intervention arm achieved a partial response (PR) and 2.7% achieved a complete response (CR). In the control arm, a PR was observed in 13.5% of patients and a CR in 2.7%. Overall, there is a statistically significant advantage in the overall response rate of trametinib in combination with dabrafenib compared with carboplatin and vincristine.
  • There are uncertainties regarding the assessment of clinical status by the medical trial staff:
  • The study protocol only specified criteria for deterioration, but not for improvement. Accordingly, a reduction in the K/LPS score of approximately 20 points was considered to indicate a deterioration in health status.
  • In view of these significant uncertainties, the G-BA considers that the available data on response, based on the RANO criteria, cannot be validly assessed with sufficient certainty. Consequently, no advantage relevant to the benefit assessment is inferred for trametinib in combination with dabrafenib.
• Morbidity – Progression-free survival
  • In the G2201 study, progression-free survival was defined as the time from randomisation to the first documented progression, assessed using the RANO criteria, or to death from any cause.
  • With trametinib in combination with dabrafenib, PFS was statistically significantly prolonged by 17.7 months compared with carboplatin in combination with vincristine.
  • It therefore remains unclear, in particular, to what extent the prolonged PFS observed with trametinib in combination with dabrafenib in the G2201 study was associated with an advantage in terms of disease-specific symptoms.
  • In summary, the available data do not indicate that the statistically significant prolongation of progression-free survival observed with trametinib in combination with dabrafenib – as assessed using the RANO criteria – is associated with an improvement in morbidity and/or quality of life.
  • The results for the PFS endpoint are therefore not taken into account.
• Morbidity – Symptoms (PROMIS PGH 7+2)
  • The ‘symptoms’ endpoint for the LGG cohort in the G2201 study was assessed using PROMIS PGH 7+2. However, the data cannot be analysed due to a response rate of < 70% in one arm and large differences in response rates between the study arms (> 15%).
• Health-related quality of life
  • Quality of life in the LGG cohort of the G2201 study was assessed using PROMIS PGH 7+2. However, the data cannot be analysed due to a response rate of < 70% in one arm and large differences in response rates between the study arms (> 15%).
• Side effects
  • In the G2201 study, all adverse events occurring from the date of informed consent until 30 days after the last dose of the study medication were classified as AEs.
  • The dossier for the benefit assessment did not present any analyses excluding AEs attributable to the underlying disease. Only tumour progression was not classified as an AE. It cannot therefore be ruled out that events related to the underlying disease are included in the observed AEs.
  • AE occurred in all patients with untreated LGG, in both the intervention and control arms.
  • No statistically significant difference was observed between the treatment groups for the SAE endpoint.
  • For the endpoints ‘severe AEs’ and ‘therapy discontinuations due to AEs’, statistically significant advantages were observed in favour of trametinib in combination with dabrafenib, which are interpreted as a clear improvement.
  • Overall, within the side effects endpoint category, there is a clear advantage of trametinib in combination with dabrafenib over carboplatin and vincristine in paediatric patients with untreated LGG.
• Overall assessment
  • For the benefit assessment, comparative data from the LGG cohort of the pivotal G2201 trial are available on overall survival, morbidity, health-related quality of life and side effects, compared with carboplatin and vincristine.
  • In the mortality endpoint category, there is no statistically significant difference between the treatment arms.
  • In the morbidity endpoint category, results are available for overall response and progression-free survival, which were assessed using the RANO criteria. However, due to major uncertainties regarding the data collected on clinical status, these results cannot be validly assessed with sufficient certainty.
  • The results on symptoms, collected using PROMIS PGH, cannot be assessed.
  • For the morbidity endpoint category, therefore, there are overall no differences relevant to the benefit assessment.
  • The results on health-related quality of life, collected using PROMIS PGH, cannot be assessed.
  • For the endpoint category ‘side effects’, there are statistically significant advantages in terms of severe AEs and treatment discontinuations due to AEs, which are assessed as a clear improvement. In detail, there are also predominantly advantages regarding specific AEs.
  • Overall, the G-BA concludes that, due to the clear advantages regarding side effects, trametinib in combination with dabrafenib offers a considerable additional benefit for paediatric patients with LGG who have not previously received treatment.

a2) Paediatric patients aged 1 year and over with a low-grade glioma (LGG) harbouring a BRAF V600E mutation who require systemic therapy – patients who have previously been treated for LGG

• Hint for a non-quantifiable additional benefit, as the scientific evidence does not permit quantification.
• Overall, the extent of the additional benefit is classified as non-quantifiable, as the scientific evidence does not permit quantification.
• mortality
  • Overall survival was defined in the X2101 study as the period from the start of treatment until death, regardless of the underlying cause of death.
  • No comparative data are available for patients who have previously been treated for LGG; consequently, no conclusion can be drawn regarding the extent of the additional benefit based on the results of study X2101.
• Morbidity – Overall Response Rate
  • The overall response rate (ORR) in the X2101 study was assessed in the same way as in the G2201 study. Response was assessed using the RANO criteria by a central, independent review committee and by the trial staff.
  • The overall response rate was 8 (25.8%) patients.
  • Essentially, the uncertainties mentioned above (see comments on ‘tumour response’ for patient group a1) apply with regard to the cut-off values, the subjective assessment by the medical trial staff and the response rates. Nevertheless, no conclusions regarding the extent of the additional benefit can be drawn from the results of the X2101 study, as there is no control group.
• Morbidity – Progression-free survival
  • In study X2101, progression-free survival was defined as the time from the date of the first dose of the investigational medicinal product until the first documented progression, assessed using RANO criteria, or death from any cause.
  • Essentially, the uncertainties mentioned above apply (see the comments on ‘progression-free survival’ for patient group a1).
  • Nevertheless, no conclusions regarding the extent of the additional benefit can be drawn from the results of the X2101 study, as there is no control group.
• Overall assessment
  • For the benefit assessment, non-comparative data from study X2101 are available for patients with LGG and a BRAF V600E mutation following prior treatment, relating to overall survival, morbidity and side effects.
  • However, due to the single-arm study design, these data do not permit a comparative assessment. Overall, the extent of the additional benefit is classified as non-quantifiable, as the scientific evidence does not allow for quantification.

b) Paediatric patients aged 1 year and over with a high-grade glioma (HGG) harbouring a BRAF V600E mutation who have previously received at least one course of radiotherapy and/or chemotherapy

• Hints of a non-quantifiable additional benefit, as the scientific evidence does not permit quantification.
• Overall, the extent of the additional benefit is classified as non-quantifiable because the scientific evidence does not permit quantification.
• mortality
  • Overall survival was defined in the G2201 study as the period from the start of treatment to death, regardless of the underlying cause of death.
  • There were 17 (41.5%) deaths. As no comparative data are available, no conclusion can be drawn regarding the extent of the additional benefit on the basis of these results.
• Morbidity – Overall Response Rate
  • The overall response rate (ORR) was the primary endpoint in the G2201 study. Response was assessed using the RANO criteria by a central, independent review committee and by the trial staff.
  • The overall response rate was 23 (56.1%) patients.
  • Essentially, the uncertainties mentioned above (see the comments on ‘tumour response’ for patient group a1) apply with regard to the cut-off values, the subjective assessment by the medical trial staff and the response rates. Nevertheless, no conclusions regarding the extent of the additional benefit can be drawn from the results for the HGG cohort from the single-arm part of the G2201 study, as there is no control group.
• Morbidity – Progression-free survival
  • In the G2201 study, progression-free survival was defined as the time from randomisation to the first documented progression or death from any cause, assessed using the RANO criteria.
  • Essentially, the uncertainties mentioned above apply (see the comments on ‘progression-free survival’ for patient group a1)). Notwithstanding this, no conclusions regarding the extent of the additional benefit can be drawn from the results for the HGG cohort from the single-arm part of the G2201 study, as there is no control group.
• Overall assessment
  • For the benefit assessment, non-comparative data from the HGG cohort of the pivotal study G2201 on overall survival, morbidity and side effects are available.
  • However, due to the single-arm study design, these data do not permit a comparative assessment. Overall, the extent of the non-quantifiable additional benefit is classified as non-quantifiable, as the scientific evidence base does not allow for quantification.

Courtesy translation only, please refer to the German original.