Table 3.
Main studies investigating the role of BRAF inhibitors in BRAF-altered primary brain tumours (predominantly harbouring BRAF V600E mutation).
| Design | Tumour | BRAF Alteration(s) | Drug | Patients (n) | Median Age | Endpoint(s) | Toxicity | Efficacy | |
|---|---|---|---|---|---|---|---|---|---|
| Drobysheva et al., 2017 [32] |
Case series | Pilocytic astrocytoma (PA) |
BRAF V600E | Dabrafenib/dabrafenib + trametinib | 2 | Pt. 1: 5-year-old Pt. 2: 1-year-old |
Tumour control rate with BRAF-inhibitors | Skin rash Fatigue |
1 near complete response 1 stable disease |
| Lassaletta et al., 2017 [28] |
Institutional series | Paediatric low-grade gliomas | BRAF V600E | BRAF-inhibitors (not specified) | 6 (patients who progressed after first-line treatment) |
/ | Clinical and genetic data | / | A significant response to treatment (49% to 80% tumour volume reduction) in all patients |
| Banerjee et al., 2017 [35] |
Phase 1 | Paediatric low-grade gliomas | KIAA1549–BRAF fusion/BRAF V600E (presence of BRAF aberrations assessed in 19/38 patients) |
Vemurafenib | 38 | 13.3 years | Recommended dose, dose-limiting toxicities, pharmacokinetics, tumour BRAF aberrations, and treatment-related changes in tumour MRI. | Skin rash Diarrhea Creatine phosphokinase elevation and of selumetinib |
Partial responses: 5/38 (13.1%) |
| Robison et al., 2018 [36] |
Phase 1 | Paediatric low-grade gliomas/other non haematological malignancies | Not specified | Binimetinib (MEK162) | 19 | 9 years | maximum tolerated dose of MEK162 | Creatine phosphokinase elevation (53%) Skin rash (47%) Lymphopenia (24%) |
Progressive disease: 4 (3 in low-grade glioma patients) Partial response: 4. Data not provided for the remaining 11 patients. |
| Del Bufalo et al., 2018 [37] |
Retrospective | Unresectable Paediatric low-grade gliomas (ganglioglioma, plemorphic xanthoastrocytoma, ganglioneurocytoma, pylocitic astrocytoma) |
BRAF V600E | Vemurafenib | 7 | 75.2 months | efficacy | Skin rash | Partial response: 3/7 Stable disease: 2/7 Complete response 1/7 Progressive disease: 1/7. Sustained response (CR, PR, SD) correlated with clinical improvement. |
| Kaley et al., 2018 [40] |
Phase 2 | Non-melanoma solid tumors and myeloma that harbours BRAFV600 mutations, including adult gliomas, such as malignant diffuse glioma (n = 11: six glioblastoma and five anaplastic astrocytoma), PXA (n = 7), anaplastic ganglioglioma (n = 3), pilocytic astrocytoma (n = 2), and high-grade glioma, not otherwise specified (n = 1) | BRAF V600E | Vemurafenib | 24 | 32 years | response rate, progression-free survival, overall survival, and safety. | Arthralgia (67%) Melanocytic nevus (38%) Palmar-plantar erythrodysesthesia (38%) Photosensitivity reaction (38%) |
Stable disease: 10/24 (41.7%) Partial response: 5/24 (20.8%) Progressive disease: 5/24 (20.8%) Complete response: 1/24 (4.2%) Not evaluable: 3/24 (12.5%) Median progression-free survival: 35 months |
| Wen et al., 2018 [41] |
Phase 2 | High-grade gliomas | BRAF V600E | Dabrafenib + trametinib | 37 | 42 years | Tumour control rate | Fatigue (35%) Headache (30%) Rash (24%) |
Partial response: 7/31 (22.6%) Complete response: 1/31 (3.2%) Median progression-free survival: 1.9 months Median overall survival: 1.7 months |
| Fangusaro et al., 2019 [33] |
Phase 2 | Pilocytic astrocytoma(group 1)NF1-related paediatric low-grade gliomas(group 2) | KIAA1549–BRAF fusion /BRAF V600E |
Selumetinib | 50(group 1: 25; group 2: 25) | Group 1: 9.2 years Group 2: 10.2 years |
Primary: partial/complete response to selumetinib Secondary: progression-free survival (PFS); association between BRAF aberrations and PFS/response; MAPK aberration analysis by whole-exome/RNA sequencing; characterisation of inter-/intra-patient variability in pharmakocynetics of selumetinib. |
Creatine phosphokinase elevation (68%) Hypoalbuminaemia (>60%) Skin rash (>50%) Anaemia (>50%) Gastric haemorrhage (>505) Liver enzymes increase (∼50%) The most frequent grade 3 or 4 adverse events were elevated CPK (5 [10%]) and maculopapular rash (5 [10%] |
Group 1 Partial response: 9/25 (36%) Stable disease 9/25 (36%) Progressive disease 7/25 (28%) 2-years PFS: 70% No association between BRAF alterations (fusion vs. mutation) and treatment response/PFS. Group 2 Stable disease: 15/25 (60%) Partial response: 9/25 (36%) Progressive disease: 1/25 (4%) 2-years PFS: 96% No association between BRAF alterations (fusion vs. mutation) and treatment response/PFS. |
| Hargrave al, 2019 [38] |
Phase 1/2 | Paediatric low-grade gliomas | BRAF V600E | Dabrafenib | 32 | 8.5 years | Safety, tolerability, and clinical activity | Fatigue (34%) Rash (31%) Dry skin (28%) Pyrexia (28%) Maculopapular rash (28%) Grade 3/4 AEs: 9 patients (28%) |
Stable disease: 16/32 (50%) Partial response: 13/32 (41%) Progressive disease: 2/32 (6%) Complete response: 1/32 (3%) Median progression-free survival: 35 months |