Tovorafenib (1) – Ojemda®

• Clinical trials
  • To assess the extent of the additional benefit of tovorafenib in the therapeutic indication for paediatric low-grade glioma (pediatric low-grade glioma, pLGG) with a BRAF fusion or rearrangement or a BRAF V600 mutation following one or more systemic therapies, the pharmaceutical manufacturer submitted, in particular, data from the pivotal, non-randomised, non-comparative, multicentre FIREFLY-1 study.
  • The FIREFLY-1 study is a Phase II trial, ongoing since 2021, comprising three cohorts designed to investigate the efficacy and safety of tovorafenib in children, adolescents and young adults (aged 6 months to 25 years) with recurrent or progressive paediatric low-grade glioma or advanced solid tumours.

Patients aged 6 months and over with paediatric low-grade malignant glioma with a BRAF fusion or rearrangement or a BRAF V600 mutation and disease progression following one or more previous systemic therapies

• Hint for a non-quantifiable additional benefit, as the scientific data do not permit quantification.
• For the assessment of the extent of the additional benefit of tovorafenib in the therapeutic indication for paediatric low-grade glioma (pediatric low-grade glioma, pLGG) with a BRAF fusion or rearrangement or a BRAF V600 mutation following one or more systemic therapies, the pharmaceutical manufacturer submitted, in particular, data from the pivotal, non-randomised, non-comparative, multicentre FIREFLY-1 study.
• As no comparative data are available, no conclusion can be drawn on the extent of the additional benefit on the basis of these results.
• mortality
  • Across the two relevant study cohorts, there were 9 (6.57%) 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
  • In the FIREFLY-1 study, the overall response rate was defined as the proportion of patients with the best confirmed overall response ( complete response, CR; partial response (PR); minor response (MR)), which was achieved from the start of treatment with tovorafenib but before the start of subsequent anti-tumour therapy.
  • The overall response rate was assessed according to the‘Response Assessment in Neuro-Oncology’(RANO) for high-grade gliomas (HGG) and low-grade gliomas (LGG) in adults, and according tothe ‘Response Assessment in Paediatric Neuro-Oncology’criteria for LGG (RAPNO-LGG) in paediatric patients.
  • No data on the individual components of the endpoint were presented.
  • The available information does not indicate which criteria were used to incorporate the assessment of patients’ clinical status into the evaluation of the overall response.
  • The overall response rate represents a relevant clinical parameter for treatment guidance in this therapeutic indication and is presented for supplementary information.
  • Notwithstanding this, no conclusion can be drawn from these results regarding the extent of the additional benefit, as no comparative data are available.
• Morbidity – Progression-free survival
  • Progression-free survival (PFS) was defined in the FIREFLY-1 study as the time from the administration of the first dose of tovorafenib to the first documented progression of the disease, assessed using the RANO-HGG, RANO-HGG criteria, RANO-LGG criteria or RAPNO-LGG criteria, or death from any cause, whichever occurs first.
  • The PFS endpoint in question is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories.
  • Given that the intended therapeutic indication here concerns patients with LGG, only data collected using the RANO and RAPNO-LGG criteria can be considered relevant for this therapeutic situation.
  • No data on the individual components were provided.
  • The same uncertainties apply to the assessment of clinical status as those described under the overall response rate.
  • Notwithstanding this, no conclusion can be drawn from these results regarding the extent of the additional benefit, as no comparative data are available.
• Morbidity – Visual acuity
  • In the FIREFLY-1 study, visual acuity was assessed using age-specific visual acuity tests (in particular Snellen eye charts, Teller Acuity charts, HOTV charts or other ‘Early Treatment Diabetic Retinopathy Study’ (EDTRS) charts).
  • The endpoint of visual acuity is considered to be patient-relevant.
  • However, the following uncertainties in particular remain. Firstly, in 35% of cases, ‘other’ procedures were used to determine visual acuity than those mentioned above; however, it remains unclear which procedures fall under the category of ‘other’.
  • Secondly, in the FIREFLY-1 study, there were patients for whom different vision tests were used over the course of the study. The extent to which the vision tests used can yield comparable results remains unclear.
  • Furthermore, it remains unclear whether all 68 patients with optic pathway glioma were included in the overall analysis of the 105 patients at the start of the study, or for what reason the additional 37 patients without a primary tumour of the optic pathway were included in the analysis at the start of the study.
  • Notwithstanding this, no conclusion can be drawn from these results regarding the extent of the additional benefit, as no comparative data are available.
• quality of life
  • PedsQL Core
  • Health-related quality of life was assessed in the FIREFLY-1 study using the PedsQL Core.
  • However, the response rates were already below 70% at baseline.
  • The data are therefore not considered usable.
  • Notwithstanding this, no conclusions can be drawn from these results regarding the extent of the additional benefit, as no comparative data are available.
• Side effects
  • In the FIREFLY-1 study, all adverse events (AEs) were recorded from the first dose of tovorafenib up to 30 days after the last dose.
  • Serious AEs and AEs of particular interest were recorded from 30 days after the last study medication until the start of a new anti-tumour therapy.
  • AE occurred in all patients.
  • Across both cohorts, severe AEs occurred in 113 (82.5%) patients and severe SAEs in 77 (56.2%) patients.
  • In total, 19 (13.9%) patients discontinued treatment with tovorafenib 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
  • Non-comparative data from the single-arm, Phase II FIREFLY trial, which formed the basis for marketing authorisation, are available for the benefit assessment, with regard to overall survival, morbidity, health-related quality of life and side effects.
  • Overall, the extent of the additional benefit is classified as non-quantifiable, as the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.