Tovorafenib

Tovorafenib is a central nervous system (CNS) penetrant, selective small-molecule Type II RAF kinase inhibitor. Paediatric low-grade glioma is often driven by BRAF alterations such as fusions or rearrangements, which hyperactivate the RAS–RAF–MEK–ERK (MAPK) signalling pathway. Tovorafenib is designed to switch that pathway off in such tumours. Efficacy was evaluated in a single-arm, open-label study (FIREFLY-1) in 76 patients aged 6 months to 25 years with relapsed or refractory low-grade glioma.

Mechanism of Action

• Targets: inhibits mutant BRAF V600E, wild-type BRAF and wild-type CRAF kinases, including RAF monomers and dimers and BRAF fusions, which suppresses activation of the MAPK pathway.
• Pathway: BRAF is activated by RAS and phosphorylates MEK1/2, which in turn phosphorylates ERK1/2 and drives cell growth, proliferation and differentiation. Oncogenic BRAF alterations leave this cascade permanently active.
• Binding mode: as a Type II inhibitor it binds the kinase in its ‘DFG-out’ conformation. It is not reported to cause paradoxical activation of the MAPK pathway.
• Preclinical activity: antitumour activity was seen in cultured cells and xenograft models with BRAF V600E and V600D mutations and in a xenograft model with a BRAF fusion.
• Exposure effects: higher exposure is associated with reduced height-for-age z-scores in children, and with a higher risk of rash, raised liver enzymes (AST, ALT) and raised creatine phosphokinase.
• Cardiac electrophysiology: at the recommended dose (380 mg/m² once weekly, maximum 600 mg), no mean increase in the QT interval of more than 20 ms was seen.

Pharmacokinetics

• Absorption: median time to peak concentration is 3 hours (range 1.5–4) after a single dose of tablets or oral suspension. A high-fat meal caused no clinically significant change in Cmax or AUC but delayed the peak to 6.5 hours, so it can be taken with or without food.
• Steady state: at the recommended dose, modelling gives a steady-state Cmax of 6.9 µg/mL and an AUC of 508 µg·h/mL. Steady state is reached after about 12 days, exposure rises in proportion to dose, and no clinically significant accumulation occurs.
• Distribution: apparent volume of distribution is about 60 L/m². It is 97.5% bound to human plasma proteins in vitro (mainly albumin) and crosses the blood-brain barrier.
• Metabolism: mainly by aldehyde oxidase and CYP2C8 in vitro; CYP3A, CYP2C9 and CYP2C19 contribute to a minor extent.
• Elimination: terminal half-life is about 56 hours and apparent clearance 0.7 L/h/m². After a radiolabelled dose, about 65% of the radioactivity was recovered in the faeces (8.6% as unchanged drug) and about 27% in the urine (0.2% unchanged).
• Special populations: see Administration and Dosage for hepatic and renal impairment.

• Paediatric low-grade glioma (LGG): monotherapy for patients 6 months of age and older with paediatric low-grade glioma harbouring a BRAF fusion or rearrangement, or a BRAF V600 mutation, who have progressed after one or more prior systemic therapies.
• Biomarker confirmation: before treatment, the BRAF fusion or rearrangement, or BRAF V600 mutation, must be confirmed with a CE-marked in vitro diagnostic medical device with the corresponding intended purpose, or, if none is available, with an alternative validated test.
• The film-coated tablets and the oral suspension have the same indication.

• Hypersensitivity to tovorafenib or to any of the excipients.

Safety data come from 137 patients aged 6 months and older with relapsed or refractory paediatric LGG and a BRAF alteration in FIREFLY-1 (median treatment 22.5 months; median age 9 years, range 1 to 24; only 3 patients, 2%, were aged 6 months to under 2 years). The most common reactions were hair colour changes (77.4%), increased blood creatine phosphokinase (62.0%), fatigue and anaemia (60.6% each), vomiting (56.2%), hypophosphataemia and headache (52.6% each), maculo-papular rash (50.4%), pyrexia (46.7%) and growth retardation (43.1%). The SmPC table has only two frequency groups.

Very common (≥1/10): upper respiratory tract infection, paronychia, viral infection; anaemia; decreased appetite, hypokalaemia, hypoalbuminaemia, hyponatraemia; headache; haemorrhage (a grouped term including epistaxis, contusion, gingival bleeding, haematoma, petechiae and gastrointestinal haemorrhage), intratumoural haemorrhage, flushing; vomiting, nausea, constipation, abdominal pain, stomatitis, diarrhoea; rash (a grouped term including maculo-papular rash and eczema), hair colour changes, dry skin, acneiform dermatitis, pruritus, skin discolouration, alopecia, photosensitivity reaction; growth retardation, pain in extremity, myalgia, arthralgia; fatigue, pyrexia, oedema; decreased blood phosphorus and increased blood creatine phosphokinase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase and bilirubin.

Common (≥1/100 to <1/10): blepharitis, dry eye.

Other laboratory findings listed in the SmPC investigations row are weight decreased, lymphocyte count decreased, white blood cell count decreased and eosinophilia; see the SmPC for their frequency groups.

Important serious reactions:

• Serious reactions: the most common were growth retardation (6.6%), vomiting (6.6%) and tumour haemorrhage (5.1%). Reactions leading to permanent discontinuation in more than one patient were growth retardation and tumour haemorrhage (2.9% each).
• Intratumoural haemorrhage: 13.9% of patients (grade 3 or higher in 3.6%; a fatal grade 5 event in 0.7%). Other haemorrhage: 40.1% of patients, most often epistaxis (32.1%, mostly grade 1).
• Growth retardation: reported in 44.5% of patients aged 18 or younger. Growth velocity recovered in patients followed after treatment was interrupted, and among those who had hand radiographs to assess bone age, no premature closure of the growth plates or advance in bone age was seen.
• Liver and muscle: raised ALT in 24.8%, AST in 38% and bilirubin in 14.6% of patients; raised creatine phosphokinase in 62% (all non-serious).
• Skin: rash in 83.2% (grade 3 or higher in 12.4%); photosensitivity in 14.6%.

• Strong or moderate CYP2C8 inhibitors (for example gemfibrozil): predicted to raise tovorafenib exposure and the risk of adverse reactions. Avoid co-administration.
• Strong or moderate CYP2C8 inducers (for example carbamazepine): predicted to lower tovorafenib exposure and efficacy. Avoid co-administration.
• CYP3A substrates: tovorafenib is a CYP3A inducer and is expected to lower the exposure of certain CYP3A substrates. Avoid it with substrates where small concentration changes could cause serious therapeutic failure (for example tacrolimus); if this cannot be avoided, monitor for loss of efficacy unless the substrate’s SmPC says otherwise.
• Hormonal contraceptives: as CYP3A substrates, they may be made ineffective. Avoid the combination; if unavoidable, use an additional effective non-hormonal method during co-administration and for 28 days after tovorafenib is stopped.
• In vitro data: tovorafenib inhibits CYP2C8, CYP2C9, CYP2C19, CYP3A, BCRP, OATP1B1, OATP1B3 and MATE1, and induces CYP3A, CYP2C8, CYP1A2, CYP2B6, CYP2C9 and CYP2C19, potentially at clinically relevant concentrations. It is not a substrate of BCRP, P-glycoprotein, OATP1B1 or OATP1B3. See section 4.5 of the SmPC for further detail.
• Food: it can be taken with or without food.

Treatment must be initiated and supervised by a qualified physician experienced in the use of anti-cancer medicinal products, after the BRAF alteration has been confirmed. Ojemda is taken by mouth once weekly at a regularly scheduled time, with or without food, and paediatric patients take it under adult supervision. The film-coated tablets and the oral suspension may be used interchangeably.

Recommended Dose

• 380 mg/m² body surface area (BSA) once weekly, with a maximum of 600 mg once weekly. A dose for patients with BSA below 0.3 m² has not been established.
• Duration: continue once weekly until disease progression, loss of clinical benefit or unacceptable toxicity.

Film-Coated Tablets (100 mg)

• BSA 0.90–1.12 m²: 400 mg once weekly.
• BSA 1.13–1.39 m²: 500 mg once weekly.
• BSA 1.40 m² or more: 600 mg once weekly.
• BSA 0.30–0.89 m²: use the powder for oral suspension.
• Swallow the tablets whole with water; they must not be chewed, cut or crushed. Patients who cannot swallow, or with BSA below 0.9 m², should be given the oral suspension.

Powder for Oral Suspension (25 mg/mL)

Dose volumes of the reconstituted 25 mg/mL suspension, once weekly, by BSA:

• 0.30–0.35 m²: 5 mL (125 mg)
• 0.36–0.42 m²: 6 mL (150 mg)
• 0.43–0.48 m²: 7 mL (175 mg)
• 0.49–0.54 m²: 8 mL (200 mg)
• 0.55–0.63 m²: 9 mL (225 mg)
• 0.64–0.77 m²: 11 mL (275 mg)
• 0.78–0.83 m²: 12 mL (300 mg)
• 0.84–0.89 m²: 14 mL (350 mg)
• 0.90–1.05 m²: 15 mL (375 mg)
• 1.06–1.25 m²: 18 mL (450 mg)
• 1.26–1.39 m²: 21 mL (525 mg)
• 1.40 m² or more: 24 mL (600 mg)

The maximum dose per bottle is 300 mg (12 mL). The powder must be reconstituted before use (see section 6.6 of the SmPC); the reconstituted suspension has a shelf life of 15 minutes. If the patient cannot swallow and has a nasogastric tube in place, the suspension can be given through the tube.

Dose Modifications for Adverse Reactions

Adverse reactions may require dose reduction, interruption or discontinuation (grades per NCI CTCAE version 5.0).

• Dose reductions for the tablets: for BSA 0.30–1.12 m², switch to the oral suspension (see its SmPC for the reduced doses). For BSA 1.13–1.39 m², the first reduction is 400 mg once weekly and the second is the oral suspension. For BSA 1.40 m² or more, the first reduction is 500 mg once weekly and the second is 400 mg once weekly. The reduced doses for the suspension are given in the SmPC of the powder for oral suspension.
• Haemorrhage and intratumoural haemorrhage: for intolerable grade 2 or grade 3, withhold; if improved to grade 0–1, resume at a reduced dose, and if not improved consider permanent discontinuation. The same applies to a first grade 4 event; discontinue permanently for a recurrent grade 4 event.
• Skin toxicity including photosensitivity: for intolerable grade 2, or grade 3 or 4, withhold; if improved to grade 0–1, resume at a reduced dose, and if not improved consider permanent discontinuation.
• Liver-related events: for grade 3 AST or ALT, or grade 3 bilirubin, withhold. Once improved to grade 2 or below (or baseline), resume at the same dose if the abnormality resolves within 8 days, or at a lower dose if it does not. For a first grade 4 event, withhold and resume at a lower dose when improved to grade 0–1 (consider discontinuation if not improved); discontinue permanently for a recurrent grade 4 event.
• Other adverse reactions: for intolerable grade 2 or grade 3, withhold and resume at a reduced dose when improved to grade 0–1, considering permanent discontinuation if not improved. For grade 4, withhold, resume at a reduced dose when improved to grade 0–1, and consider discontinuation if not improved.

Special Populations

• Hepatic impairment: no adjustment for mildly abnormal liver function tests (bilirubin up to the upper limit of normal with raised AST, or bilirubin above 1 and up to 1.5 times the limit with any AST). Not studied with moderately (bilirubin above 1.5 and up to 3 times the limit) or severely (above 3 times) abnormal tests; monitor these patients carefully.
• Renal impairment: no adjustment for mild to moderate impairment (eGFR 30 mL/min/1.73 m² or more). Not studied in severe impairment.
• Children: paediatric clinical experience is limited, particularly between 6 months and 2 years of age. Safety and efficacy below 6 months have not been established, and no data are available.

Missed or Vomited Dose

• If a dose is missed by 3 days or less, take it as soon as possible and take the next dose on its regular day. If it is missed by more than 3 days, skip it and take the next dose on its regular day. At least 4 days must separate doses.
• If vomiting occurs immediately after a dose, repeat the dose.

Intratumoural and Other Haemorrhage

Haemorrhagic events, including intratumoural and intracranial tumour haemorrhage, are very common. Concomitant anticoagulants and antiplatelet therapy may increase the risk. Patients and caregivers should be told of the risk, and signs and symptoms of bleeding should be monitored routinely. Manage events with dose interruption, dose reduction or discontinuation.

Effect on Growth

Reductions in growth velocity are very common. Monitor growth and development before starting, routinely during treatment and after it has stopped.

Liver Function

Check AST, ALT and bilirubin before starting, 1 month after starting and routinely during treatment. Withhold treatment and resume at the same or a reduced dose after improvement, or discontinue permanently, depending on severity.

Skin Toxicity and Photosensitivity

Monitor for new or worsening skin reactions and consider dermatological consultation and supportive care. Patients and caregivers should be advised to protect against ultraviolet exposure with sunscreen (SPF 50 or higher), sunglasses and protective clothing.

Neurofibromatosis Type 1 (NF1)

Non-clinical data in NF1 models without BRAF alterations suggest tovorafenib may promote tumour growth in patients with NF1-associated tumours, so a BRAF alteration must be confirmed before treatment.

Contraception, Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should have a pregnancy test before starting and must use effective non-hormonal contraception, such as a barrier method, during therapy and for 28 days after the last dose, because tovorafenib may reduce the efficacy of hormonal contraceptives. Male patients with female partners of reproductive potential must use condoms and effective contraception during treatment and for 2 weeks after the last dose.
• Pregnancy: there are no data in pregnant women, and animal studies have shown reproductive toxicity. It should not be given to pregnant women unless the potential benefit to the mother outweighs the possible risk to the foetus.
• Breastfeeding: it is not known whether tovorafenib passes into human milk. Breastfeeding should be discontinued during treatment and for 2 weeks after the last dose.
• Fertility: there are no human data. Animal findings suggest it may affect fertility in males and females and that this may not be reversible.

Excipients

Each 100 mg tablet contains less than 1 mmol (23 mg) sodium, that is to say it is essentially ‘sodium-free’.

Effect on Driving

Tovorafenib has a minor influence on the ability to drive and use machines. Patients should be aware that it can cause fatigue.

Ojemda tablets and powder for oral suspension do not require any special storage conditions. The tablets are supplied in blisters (PCTFE laminated between PVC, with aluminium foil backing) of 4, 5 or 6 tablets, in cartons of 16, 20 or 24 tablets; not all pack sizes may be marketed.

• Film-coated tablets: 3 years.
• Powder for oral suspension: 3 years.
• Reconstituted oral suspension: 15 minutes.

Prescription only (Rx), on restricted medical prescription. Treatment must be started and supervised by a qualified physician experienced in the use of anti-cancer medicinal products. Children take Ojemda at home once weekly under adult supervision, so the tablets and the powder for oral suspension are supplied on prescription to the patient’s family or carers, or to the treating clinic.