Source: European Medicines Agency (EU) Revision Year: 2026 Publisher: Ipsen Pharma, 70 rue Balard, 75015 Paris, France
Pharmacotherapeutic group: Antineoplastic agent, protein kinase inhibitor, B-Raf serine-threonine kinase (RAF) inhibitor
ATC code: L01EC04
Tovorafenib is a central nervous system (CNS)-penetrant, selective small molecule Type II RAF kinase inhibitor of mutant BRAF V600E, wild-type BRAF, and wild-type CRAF kinases, including RAF monomers and dimers and BRAF fusion, suppressing activation of the mitogen-activated protein kinase (MAPK) pathway (see section 5.3).
At the recommended tovorafenib dose of 380 mg/m² orally once weekly (not to exceed 600 mg), a mean increase in the QT interval >20 milliseconds was not observed.
The efficacy of tovorafenib was evaluated in patients 6 months of age and older in a multicentre, open-label, single-arm clinical study (FIREFLY-1 [Arm 1]). Eligible patients (n=76), from 6 months to 25 years of age, were required to have a relapsed or refractory paediatric low-grade glioma (LGG) harbouring an activating BRAF alteration based on local laboratory testing. Patients were also required to have at least one measurable lesion as defined by RANO 2010 criteria. All patients had received at least one line of prior systemic therapy and had documented evidence of radiographic progression.
Patients with tumours harbouring additional activating molecular alteration(s) (e.g., IDH1/2 mutations, FGFR mutations) or patients with known or suspected diagnosis of neurofibromatosis type 1 (NF1) were excluded.
Patients received tovorafenib approximately 420 mg/m² orally once weekly (range: 290 to 476 mg/m², 0.76-1.25 times the recommended dose) according to body surface area with a maximum dose of 600 mg until disease progression, loss of clinical benefit, or unacceptable toxicity.
Tumour assessments were performed every 12 weeks. The major efficacy endpoints were overall response rate (ORR) of patients assessed by independent review based on RANO-HGG (Response Assessment in Neuro-Oncology for High-Grade Glioma), the primary endpoint, and RAPNO-LGG (Response Assessment in Paediatric Neuro-Oncology) criteria. Additional efficacy outcome measures were duration of response, time to response, ORR and progression-free survival (PFS) by independent review based on RANO-LGG (2011) criteria. The median age was 8.5 years (range: 2 to 21 years); 14 patients were below 6 years old, 42 between 6 and 12 years old, 15 between 12 and 16 years old and 6 patients older than 16, and below 25 years-old; 53% were male; 61% were White, and 93% had Karnofsky/Lansky performance status of 80 to 100. Patients received a median of 3 prior systemic regimens (range: 1 to 9), including 22%, 26%, 21%, and 30% who received 1, 2, 3, and >3 prior systemic regimens, respectively. Most common prior systemic therapies were chemotherapy regimens (carboplatin and vincristine). 46 patients (60%) received prior treatment with a MAP kinase pathway inhibitor. The most common tumour locations were the optic pathway (51%), deep midline structures (12%), brain stem (8%), cerebellum (7%), and cerebral hemisphere (5%). 63 patients (83%) had a BRAF fusion or rearrangement and 13 patients (17%) had a V600 mutation.
The median duration of treatment was 23.7 months (range: 0.7 to 32.1 months). Per protocol, patients could also enter an optional drug holiday after completing 26 cycles of therapy/24 months of treatment and at the investigator discretion: 43% (33/76) patients were on a drug holiday, 14% (11/76) patients remained on treatment. Out of the patients who entered a drug-holiday, 3 patients (9.1%) were retreated with tovorafenib following clinical or radiographic evidence of disease progression.
Based on RANO-HGG criteria per independent review, out of the 69 evaluable patients, the ORR was 71.0% (58.8, 81.3; 95% CI), with 23.2% of patients were in complete response, 47.8% in partial response and 21.7% in stable disease. The median duration of response was 19.7 months (95% CI: 13.7, NE [not estimable]).
Efficacy results based on RAPNO-LGG are shown in Table 5.
Table 5. Efficacy results based on independent review in FIREFLY-1 (Arm-1):
| Efficacy parameter | RAPNO-LGG N=76* |
| Overall response rate | |
| ORR (CR+PR+MR) 95% CIa | 52.6% (40.8, 64.2) |
| Best overall response | |
| Complete response (CR), n (%) | 0 (0) |
| Partial response (PR), n (%) | 29 (38.2%) |
| Minor response (MR), n (%) | 11 (14.5%) |
| Stable disease (SD), n (%) | 22 (28.9%) |
| Progressive disease (PD), n (%) | 13 (17.1%) |
| Duration of response (DoR) | N=40 |
| Median (95% CI)b, months | 18.0 (12.0, 22.8) |
| DoR rate at ≥12 months (95% CI)b | 65.0% (48.2%, 77.6%) |
| DoR rate at ≥24 months (95% CI)b | 25.6% (11.4%, 42.6%) |
Abbreviations: RAPNO-LGG = Response Assessment in Paediatric Neuro-Oncology for Low-Grade Glioma; CI = confidence interval.
* At least one measurable lesion by the relevant imaging criteria at baseline based on RAPNO-LGG
a Based on Clopper-Pearson exact confidence interval.
b Based on Kaplan-Meier estimate.
The European Medicines Agency has deferred the obligation to submit the results of FIREFLY-2 study until July 2030 with Ojemda in one or more subsets of the paediatric population in the treatment of paediatric low-grade glioma (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
Tovorafenib pharmacokinetic parameters are presented as mean (CV%) unless otherwise indicated. Based on pop-PK modelling, tovorafenib steady state maximum concentration (Cmax) is 6.9 μg/ml (23%) and the area under the concentration-time curve (AUC) is 508 μg.h/ml (31%). Time to reach steady state of tovorafenib is 12 days (33%). Tovorafenib exposure increases in a dose-proportional manner. No clinically significant tovorafenib accumulation occurs.
Based on clinical study in healthy volunteers, tovorafenib median (minimum, maximum) time to achieve peak plasma concentration (Tmax) is 3 hours (1.5, 4 hours), following a single dose with tablets or oral suspension.
Based on clinical study in healthy volunteers, no clinically significant differences in tovorafenib Cmax and AUC were observed following administration of tablets with a high-fat meal (approximately 859 total calories, 54% fat) compared to fasted conditions, but the Tmax was delayed to 6.5 hours.
Based on pop-PK modelling, tovorafenib apparent volume of distribution is 60 L/m² (23%). Tovorafenib is 97.5% bound to human plasma proteins in vitro. Tovorafenib is highly protein-bound to albumin (≈95%) and moderately bound to alpha-1 acid glycoprotein (AAG) (≈42%).
Tovorafenib is primarily metabolised by aldehyde oxidase and CYP2C8 in vitro. CYP3A, CYP2C9 and CYP2C19 metabolise tovorafenib to a minor extent.
In vitro studies:
CYP450 enzymes: Tovorafenib inhibits CYP2C8, CYP2C9, CYP2C19 and CYP3A, but does not inhibit CYP1A2, CYP2B6 and CYP2D6 potentially at clinically relevant concentrations. Tovorafenib induces CYP3A, CYP2C8, CYP1A2, CYP2B6, CYP2C9 and CYP2C19 potentially at clinically relevant concentrations.
Transporter systems: Tovorafenib is not a substrate of breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), OATP1B1 and OATP1B3. Tovorafenib has not been evaluated as a substrate of OAT1, OAT3, MATE1, MATE2-K and OCT2. Tovorafenib inhibits BCRP, OATP1B1, OATP1B3 and MATE1 potentially at clinically relevant concentrations.
Based on pop-PK modelling, tovorafenib terminal half-life is approximately 56 hours (33%) and the apparent clearance is 0.7 L/h/m² (31%). Based on clinical study in healthy volunteers, following a single oral dose of radiolabelled tovorafenib, 66.1% of the total radiolabelled dose was recovered in the faeces (8.6% unchanged) and 28.7% of the dose was recovered in the urine (0.2% unchanged).
Based on pop-PK modelling, no clinically significant differences in the pharmacokinetics of tovorafenib were observed based on age (range: 1 to 94 years). Cmax and AUC in paediatric patients aged 11 months to 17 years were within the range of values observed in adults given the same dose per body surface area.
Based on pop-PK modelling, no clinically significant differences of tovorafenib were observed in patients with mild-to-moderate renal impairment (eGFR ≥30 ml/min/1.73 m² calculated by Schwartz equation or MDRD equation). Tovorafenib has not been studied in patients with severe (eGFR <30 ml/min/1.73 m²) renal impairment.
Based on pop-PK modelling of PK data derived from clinical studies, no clinically significant differences of tovorafenib were observed in patients with mildly abnormal liver functions tests (defined as bilirubin ≤ upper limit of normal [ULN] and Aspartate Aminotransferase (AST) > ULN or bilirubin > 1 to 1.5x ULN and any AST). Tovorafenib has not been studied in patients with moderately abnormal liver functions tests (defined as bilirubin > 1.5x to 3x ULN and any AST) or severely abnormal liver functions tests (defined as total bilirubin > 3 x ULN and any AST) (see section 4.2).
No clinically significant differences in the pharmacokinetics of tovorafenib were observed based on race (White, Black, Asian).
No clinically significant differences in the pharmacokinetics of tovorafenib were observed based on sex.
Tovorafenib exposure is associated with reduction in height-for-age Z-scores in paediatric patients. Reduced height-for-age risk persists during treatment with tovorafenib. Higher tovorafenib exposure was associated with increased risk of adverse reactions such as skin rash and elevated liver enzymes (AST and ALT) (see section 4.8). The exposure-response relationship for overall response rate based on RAPNO-LGG was not clinically significant over the dose range of 290 to 476 mg/m² (0.76-1.25 times the recommended dose).
In vitro, tovorafenib increased phosphorylation of extracellular signal-regulated kinase (ERK) at clinically relevant concentrations in cells with neurofibromatosis Type 1loss of function (NF1-LOF) suggesting activation, rather than inhibition, of the MAP kinase pathway. In an NF1 genetically engineered mouse model of plexiform neurofibroma without BRAF alteration, tovorafenib did not have antitumour activity (see section 4.4) and while not statistically significant, an increase in tumour volume was noted in 2/12 mice (approximately 17%).
In hERG-transfected HEK293 cells, hERG channel was inhibited indicating potential for QT prolongation. Half-maximal inhibitory concentration was 8.9 μM which is 32-fold higher than the clinical plasma unbound concentration in adults.
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows: Tovorafenib was not carcinogenic in a 26-week (or 6-month) study in transgenic mice at exposures approximately 0.6-fold the human exposure (AUC) at the recommended human dose. Based on in vitro and in vivo studies, tovorafenib is not considered genotoxic at clinically relevant exposures. In a preliminary embryofetal development study in rats, total litter loss due to early resorptions was observed in all females at exposure levels lower than the recommended dose in human. This resulted in no foetus available for further examination, and explains the absence of further developmental studies (pivotal embryofetal development studies and prenatal and postnatal development study). In a fertility and early embryonic development study in female rats, tovorafenib decreased the number of pregnancies, corpora lutea, and live embryos, as well as increased post-implantation losses at doses as low as approximately 0.8-fold the human exposure at the recommended dose based on AUC.
In repeat-dose toxicology studies in rats of up to 3 months duration, tovorafenib-related findings in female rats included reversible increased thickness of the vaginal mucosa, increased size and/or numbers of corpora haemorrhagicum and haemorrhage, and non-reversible cystic follicles, decreased corpora lutea, and interstitial cell hyperplasia were observed in ovaries at doses approximately 0.4-fold the human exposure at the recommended dose based on AUC. In male rats, tovorafenib reduced weights of epididymis and testes, which correlated with reversible tubular degeneration/atrophy of the testes and reduced epididymal sperm at doses approximately 0.3-fold the human exposure at the recommended dose based on AUC.
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