Dabrafenib (Finlee, 1) – Finlee®

• Clinical trials
  • The G2201 trial is a multicentre, open-label Phase II trial comprising two cohorts, designed to investigate the efficacy and safety of dabrafenib in combination with trametinib 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 study comprising four parts, designed to investigate dabrafenib in combination with trametinib in children and adolescents with recurrent or refractory solid tumours following at least one prior line of treatment, with parts C and D being used for benefit assessment.

a1) Paediatric patients aged 1 year and over with a low-grade glioma (LGG) carrying a BRAF V600E mutation who require systemic therapy – patients who have not previously received treatment for their LGG

• Consequently, the G-BA has determined that dabrafenib in combination with trametinib offers a considerable additional benefit.
• The certainty of the evidence for the established extent of the additional benefit 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.
  • The overall response rate was defined as follows: the proportion of patients with a confirmed partial response (PR) or complete response (CR) as their best response.
  • When examining the results for the overall response rate, 52.1% of patients in the intervention arm achieved a PR, and 2.7% achieved a 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 dabrafenib in combination with trametinib compared with carboplatin and vincristine.
  • There are uncertainties regarding the assessment of clinical status by the clinical trial staff: the study protocol only specified criteria for deterioration, but not for improvement.
  • Due to 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 dabrafenib in combination with trametinib.
• 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 dabrafenib in combination with trametinib, 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 with dabrafenib in combination with trametinib 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 dabrafenib in combination with trametinib – 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.
  • For the endpoints of severe AEs and therapy discontinuations due to AEs, statistically significant advantages were observed in favour of dabrafenib in combination with trametinib, which are interpreted as a clear improvement.
  • In detail, statistically significant advantages in favour of dabrafenib in combination with trametinib were observed for specific AEs relating to ‘disorders of the blood and lymphatic system’, ‘gastrointestinal disorders’, ‘investigations’, ‘decreased neutrophil count’ and ‘decreased white blood cell count’, as well as specific advantages and disadvantages regarding AEs of particular interest.
  • Overall, within the ‘side effects’ endpoint category, there is a clear advantage of dabrafenib in combination with trametinib 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 with regard to specific AEs.
  • Overall, the G-BA concludes that, due to the clear advantages regarding side effects, there is a considerable additional benefit from dabrafenib in combination with trametinib for paediatric patients with LGG who have not received prior 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

• Overall, there is a hint of a non-quantifiable additional benefit of dabrafenib in combination with trametinib, 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 the X2101 study.
• Morbidity – Overall Response Rate
  • The overall response rate (ORR) in study X2101 was assessed in the same way as in study G2201. Response was assessed according to the RANO criteria by a central, independent review committee and by the trial staff.
  • The overall response rate was operationalised in the same way as in the G2201 study (see the comments above on ‘tumour response’ in patient group a1).
  • The overall response rate was 8 (25.8%) patients.
  • Essentially, the uncertainties mentioned above (see comments on ‘tumour response’ for patient group a1) persist with regard to the cut-off values, the subjective assessment by the medical trial staff and the response rates. Nevertheless, no conclusions can be drawn from the results of study X2101 regarding the extent of the additional benefit, 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 can be drawn from the results of the X2101 study regarding the extent of the additional benefit, as there is no control group.
• Health-related quality of life
  • No data on health-related quality of life were collected in study X2101.
• Side effects
  • In the X2101 study, AEs occurred in all patients with previously treated LGG; 22 (61.1%) experienced a severe AE (SAE) and 15 (41.7%) experienced a severe unanticipated event (SAE). In total, 8 (22.2%) patients discontinued the study medication due to AEs.
  • As no comparative data are available, it is not possible to draw any conclusions regarding the extent of the additional benefit for paediatric patients with previously treated LGG on the basis of these results.
• 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

• Overall, there is a hint of a non-quantifiable additional benefit of dabrafenib in combination with trametinib, as the scientific evidence does not permit quantification.
• mortality
  • In the G2201 study, overall survival was defined 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 from these results regarding the extent of the additional benefit.
• 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.
  • The overall response rate was the primary endpoint of the G2201 trial and was defined as follows: the proportion of patients with a confirmed partial response (PR) or complete response (CR) as their best response.
  • 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. Notwithstanding this, no conclusions can be drawn regarding the extent of the additional benefit 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)). 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.
• Health-related quality of life
  • No data on health-related quality of life were collected in the HGG cohort of the G2201 study.
• Side effects
  • In the G2201 study, all adverse events occurring from the day of informed consent until 30 days after the last dose of the study medication were classified as AEs.
  • All patients experienced AEs. Severe AEs occurred in 28 (68.3%) patients, and very severe AEs in 30 (73.2%) patients. In total, 2 (4.9%) patients discontinued treatment with dabrafenib in combination with trametinib due to AEs.
  • As no comparative data are available, no conclusion can be drawn from these results regarding the extent of the additional benefit.
• Overall assessment
  • For the benefit assessment, non-comparative data from the HGG cohort of the pivotal G2201 trial 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 does not allow for quantification.

Courtesy translation only, please refer to the German original.