Dabrafenib

Dabrafenib is an inhibitor of RAF kinases with strong activity against BRAF carrying activating mutations at codon 600. Oncogenic BRAF mutations keep the RAS/RAF/MEK/ERK (MAPK) signalling pathway switched on, which drives cell-cycle progression and proliferation and blocks cell death. BRAF mutations occur in about 50% of melanomas, and V600E accounts for about 90% of them. In the combination used in most indications, dabrafenib blocks RAF and trametinib blocks MEK, two kinases in the same pathway.

Mechanism of Action

• BRAF inhibition: dabrafenib binds competitively in the ATP pocket of the kinase and has a higher affinity for mutant BRAF than for wild-type BRAF. In biochemical assays the concentration giving 50% inhibition was 0.65 nM for BRAF V600E, 0.50 nM for V600K, 1.8 nM for V600D, 3.2 nM for wild-type BRAF and 5.0 nM for wild-type CRAF.
• Effect on tumour signalling: dabrafenib suppressed phosphorylated ERK, a downstream marker, and inhibited the growth of BRAF V600-mutant melanoma cell lines in vitro and in animal models. In patients with BRAF V600-positive melanoma it lowered tumour phosphorylated ERK compared with baseline.
• Combination with trametinib: trametinib is a reversible, highly selective allosteric inhibitor of MEK1 and MEK2 activation and kinase activity. Blocking RAF and MEK together showed antitumour activity in BRAF V600-mutant melanoma cell lines and delayed the emergence of resistance in melanoma xenografts.
• Wild-type BRAF and RAS: in BRAF wild-type cells that carry RAS mutations, BRAF inhibitors can paradoxically activate MAP kinase signalling, which is why new cutaneous and non-cutaneous cancers can occur (see Special Instructions). Efficacy and safety have not been established in tumours with wild-type BRAF.

Pharmacokinetics

• Absorption: the median time to peak concentration is 2 hours and absolute oral bioavailability is 95%. After a single dose, exposure rose in proportion to dose between 12 and 300 mg, but less than proportionally with repeated twice-daily dosing. Exposure falls with repeat dosing, probably because dabrafenib induces its own metabolism (day 18 to day 1 AUC ratio 0.73). After 150 mg twice daily, the geometric mean peak concentration was 1,478 ng/mL, the AUC over a dosing interval 4,341 ng·h/mL and the pre-dose concentration 26 ng/mL. Taking the capsules with food lowered peak concentration by 51% and AUC by 31% and delayed absorption compared with fasting.
• Distribution: 99.7% bound to plasma proteins; the steady-state volume of distribution after an intravenous microdose was about 46 L. Dabrafenib is an in vitro substrate of P-glycoprotein and BCRP; DrugBank links these efflux transporters to restricted distribution into the brain.
• Metabolism: mainly by CYP2C8 and CYP3A4 to hydroxy-dabrafenib, which CYP3A4 oxidises further to carboxy-dabrafenib. Carboxy-dabrafenib is excreted in bile and urine or decarboxylated non-enzymatically to desmethyl-dabrafenib; this can also form in the gut, be reabsorbed, and is metabolised by CYP3A4. Metabolite-to-parent AUC ratios after repeat dosing were 0.9, 11 and 0.7 for hydroxy-, carboxy- and desmethyl-dabrafenib. Hydroxy- and desmethyl-dabrafenib probably contribute to the clinical activity; carboxy-dabrafenib probably does not.
• Elimination: the mean terminal half-life is about 8 hours after an oral dose. Hydroxy-dabrafenib has a similar half-life (10 hours), and the carboxy and desmethyl metabolites 21–22 hours. Faeces are the main route (71% of radioactivity), with 23% in urine as metabolites only (DrugBank). Clearance roughly doubled after two weeks of twice-daily dosing (from 17.0 to 34.4 L/h), in line with self-induction.
• Special populations: no dose adjustment is needed for mild or moderate renal impairment, mild hepatic impairment, age over 65 years or Asian ancestry. Moderate or severe hepatic impairment may raise exposure, because hepatic metabolism and biliary secretion are the main routes of elimination.

Tafinlar (hard capsules) is indicated for:

• Melanoma: alone or in combination with trametinib, for adults and adolescents aged 12 years and older with unresectable or metastatic melanoma with a BRAF V600 mutation.
• Adjuvant treatment of melanoma: in combination with trametinib, for adults and adolescents aged 12 years and older with stage III melanoma with a BRAF V600 mutation, following complete resection.
• Non-small cell lung cancer (NSCLC): in combination with trametinib, for adults with advanced NSCLC with a BRAF V600 mutation.
• Differentiated thyroid cancer (DTC): in combination with trametinib, for adults with locally advanced or metastatic DTC with a BRAF V600E mutation, refractory to or not eligible for radioactive iodine (RAI), who have progressed during or after prior systemic therapy.

Finlee (dispersible tablets, EU authorisation November 2023) is indicated, in combination with trametinib, for paediatric patients aged 1 year and older with:

• Low-grade glioma (LGG): with a BRAF V600E mutation, who require systemic therapy.
• High-grade glioma (HGG): with a BRAF V600E mutation, who have received at least one prior radiation and/or chemotherapy treatment.

• Hypersensitivity to dabrafenib or to any of the excipients (Tafinlar and Finlee).
• When dabrafenib is combined with trametinib, the trametinib SmPC must be consulted before treatment starts.

The reactions below come from clinical studies and post-marketing experience. With dabrafenib alone (578 patients with BRAF V600-mutant melanoma given 150 mg twice daily), the most common reactions (at least 15%) were hyperkeratosis, headache, pyrexia, arthralgia, fatigue, nausea, papilloma, alopecia, rash and vomiting. With dabrafenib plus trametinib (1,188 adults with melanoma, adjuvant melanoma, lung cancer or thyroid cancer; mean treatment duration 16 months), the most common reactions (at least 20%) were pyrexia, fatigue, nausea, rash, chills, diarrhoea, headache, arthralgia, vomiting, cough, haemorrhage and peripheral oedema.

Frequencies for dabrafenib with trametinib in adults:

Very common (≥1/10): nasopharyngitis, urinary tract infection, neutropenia, anaemia, decreased appetite, headache, dizziness, hypertension, haemorrhage, cough, abdominal pain, constipation, diarrhoea, nausea, vomiting, dry skin, pruritus, rash, erythema, acneiform dermatitis, arthralgia, myalgia, pain in the extremities, muscle spasms, fatigue, chills, asthenia, peripheral oedema, pyrexia, influenza-like illness, raised alanine and aspartate aminotransferases, weight increase (reported only in paediatric patients).

Common (≥1/100 to <1/10): cellulitis, folliculitis, paronychia, pustular rash, cutaneous squamous cell carcinoma, papilloma, seborrhoeic keratosis, thrombocytopenia, leukopenia, dehydration, hyponatraemia, hypophosphataemia, hyperglycaemia, peripheral neuropathy, blurred vision, visual impairment, uveitis, reduced ejection fraction, bradycardia, hypotension, lymphoedema, pneumonitis, dyspnoea, dry mouth, stomatitis, generalised exfoliative dermatitis, actinic keratosis, night sweats, hyperkeratosis, alopecia, palmar-plantar erythrodysaesthesia syndrome, skin lesions, hyperhidrosis, panniculitis, skin fissures, photosensitivity, renal failure and acute kidney injury, mucosal inflammation, facial oedema, raised alkaline phosphatase, gamma-glutamyltransferase and creatine phosphokinase, potentiation of radiation toxicity.

Uncommon (≥1/1,000 to <1/100): new primary melanoma, skin tags (acrochordon), hypersensitivity, sarcoidosis, chorioretinopathy, retinal detachment, periorbital oedema, heart failure, left ventricular dysfunction, atrioventricular block, gastrointestinal perforation, pancreatitis, colitis, acute febrile neutrophilic dermatosis, rhabdomyolysis.

Rare (≥1/10,000 to <1/1,000): haemophagocytic lymphohistiocytosis, interstitial lung disease, nephritis.

Not known: tumour lysis syndrome, myocarditis, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS), tattoo-associated skin reactions.

With dabrafenib alone, the very common reactions are papilloma, decreased appetite, headache, cough, nausea, vomiting, diarrhoea, hyperkeratosis, alopecia, rash, palmar-plantar erythrodysaesthesia syndrome, arthralgia, myalgia, pain in the extremities, pyrexia, fatigue, chills and asthenia. Common reactions include cutaneous squamous cell carcinoma, basal cell carcinoma, seborrhoeic keratosis, skin tags, hypophosphataemia, hyperglycaemia, peripheral neuropathy, constipation, dry skin, pruritus, actinic keratosis, skin lesions, erythema, photosensitivity, influenza-like illness and potentiation of radiation toxicity. Uncommon reactions are new primary melanoma, hypersensitivity, uveitis, pancreatitis, acute febrile neutrophilic dermatosis, panniculitis, renal failure or acute kidney injury and nephritis.

In children given Finlee with trametinib (171 paediatric patients in two studies, mean treatment duration 2.3 years), reactions reported by at least 20% were pyrexia (70%), rash (49%), headache (47%), vomiting (40%), fatigue (36%), dry skin (35%), diarrhoea (34%), haemorrhage (34%), nausea (29%), acneiform dermatitis (29%), abdominal pain (28%), neutropenia (26%), cough (24%) and raised transaminases (22%). The most frequent severe (grade 3 or 4) reactions were neutropenia (15%), pyrexia (11%), raised transaminases (6%) and weight increase (5%). Long-term data on growth and skeletal maturation in children are limited. The profile was largely consistent with adults, although several reactions have so far been reported only in adults.

Important serious reactions include new cutaneous and non-cutaneous cancers (cutaneous squamous cell carcinoma occurred in 10% of patients on dabrafenib alone in a Phase III melanoma study and in about 2% on the combination), pyrexia, haemorrhage (including fatal events), reduced left ventricular ejection fraction (8% on the combination, mostly symptomatic and reversible), uveitis and other eye inflammation, hypertension, pancreatitis, renal failure, venous thromboembolism, severe skin reactions, colitis and gastrointestinal perforation, haemophagocytic lymphohistiocytosis and tumour lysis syndrome. Arthralgia was reported in 25% of patients on dabrafenib alone and 25% on the combination, and hypophosphataemia in 7% and 4%, about half of the cases being grade 3.

Dabrafenib is cleared by CYP2C8 and CYP3A4 and is itself an inducer of drug-metabolising enzymes, so it is both affected by and affects many medicines. A drug utilisation review is essential before starting.

• Strong CYP2C8 or CYP3A4 inhibitors (ketoconazole, gemfibrozil, nefazodone, clarithromycin, ritonavir, saquinavir, telithromycin, itraconazole, voriconazole, posaconazole, atazanavir): use with caution, and consider alternatives where possible. Ketoconazole raised dabrafenib AUC by 71% and peak concentration by 33% (hydroxy- and desmethyl-dabrafenib AUC by 82% and 68%). Gemfibrozil raised AUC by 47% without changing peak concentration.
• Potent CYP2C8 or CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, phenobarbital, St John’s wort): avoid. Rifampicin lowered repeat-dose peak concentration by 27% and AUC by 34%.
• Dabrafenib as an enzyme inducer: it can reduce the effect of many commonly used medicines. Sensitive substrates of the affected enzymes or transporters should generally be avoided unless efficacy can be monitored and the dose adjusted.
• Hormonal contraceptives: dabrafenib may reduce the efficacy of oral or any systemic hormonal contraceptives, so an effective alternative method is needed.
• Warfarin: exposure to warfarin falls. Extra INR monitoring is advised when starting dabrafenib and when stopping it.
• Digoxin: exposure to digoxin may fall. Extra digoxin monitoring is advised when starting and stopping dabrafenib.
• Radiotherapy: radiation recall and radiation sensitisation have been reported, so use caution when radiotherapy is given at the same time or in sequence.
• Food and herbal products: take dabrafenib at least 1 hour before or 2 hours after a meal, because food lowers exposure. Avoid grapefruit products (CYP3A4 inhibition, per DrugBank) and St John’s wort.

Treatment must be started and supervised by a qualified physician experienced in the use of anti-cancer medicinal products. Before the first dose, the tumour BRAF V600 mutation (BRAF V600E for thyroid cancer and glioma) must be confirmed with a CE-marked in vitro diagnostic (IVD) medical device with the corresponding intended purpose; if none is available, an alternative validated test is used. Dabrafenib is taken by mouth.

Recommended Dose: Tafinlar Hard Capsules

• Adults: 150 mg (two 75 mg capsules) twice daily, regardless of body weight.
• Adolescents aged 12 to under 18 years with melanoma: dosed by body weight, twice daily. 26 to 37 kg: 75 mg; 38 to 50 kg: 100 mg; 51 kg or more: 150 mg. No dose has been established for patients under 26 kg.
• Trametinib: the dose of trametinib is given in its own SmPC.
• Duration: until the patient no longer benefits or unacceptable toxicity develops. In adjuvant melanoma, treatment lasts 12 months unless the disease recurs or toxicity is unacceptable.

Recommended Dose: Finlee Dispersible Tablets (Children)

Finlee is used with trametinib powder for oral solution (see its SmPC for the trametinib dose). The twice-daily dose depends on body weight, rounded to the nearest kg, using 10 mg tablets:

• 8 to 9 kg: 20 mg (2 tablets)
• 10 to 13 kg: 30 mg (3 tablets)
• 14 to 17 kg: 40 mg (4 tablets)
• 18 to 21 kg: 50 mg (5 tablets)
• 22 to 25 kg: 60 mg (6 tablets)
• 26 to 29 kg: 70 mg (7 tablets)
• 30 to 33 kg: 80 mg (8 tablets)
• 34 to 37 kg: 90 mg (9 tablets)
• 38 to 41 kg: 100 mg (10 tablets)
• 42 to 45 kg: 110 mg (11 tablets)
• 46 to 50 kg: 130 mg (13 tablets)
• 51 kg or more: 150 mg (15 tablets)

No dose has been established under 8 kg. Finlee must not be replaced with other dabrafenib formulations, because bioequivalence was not shown. Treatment continues until disease progression or unacceptable toxicity. Data beyond 18 years of age are limited, so continuing into adulthood depends on the individual benefit and risk. The tablets are dispersed to make a suspension, which must be used within 30 minutes of preparation (preparation instructions are in the SmPC and package leaflet).

Dose Adjustments

• Side effects may require interruption, dose reduction or discontinuation. The 50 mg and 75 mg capsules allow stepwise reductions, and the SmPC tables give the dose levels and the rules for each reaction. With Finlee, when treatment-related toxicity occurs, dabrafenib and trametinib are reduced, interrupted or stopped together.
• Skin cancers: no dose change is recommended for cutaneous squamous cell carcinoma or new primary melanoma.
• Uveitis: no change if local therapy controls the inflammation. If it does not respond, dabrafenib is withheld until it resolves and then restarted one dose level lower.
• Fever, pulmonary embolism, severe skin reactions and haemophagocytic lymphohistiocytosis: see Special Instructions.

Special Populations

• Renal impairment: no adjustment for mild or moderate impairment. There are no clinical data in severe impairment, so use with caution.
• Hepatic impairment: no adjustment for mild impairment. There are no clinical data in moderate or severe impairment, so use with caution.
• Elderly: no adjustment of the initial dose over 65 years.
• Race: limited data in non-Caucasian patients; no adjustment is needed in Asian patients.
• Children: the safety and efficacy of the capsules below 18 years have not been established, except in adolescents aged 12 years and older with melanoma. Studies in juvenile animals showed effects not seen in adult animals. Finlee is for glioma from 1 year of age.

Missed Dose

A missed dose of dabrafenib (capsules or Finlee) is taken only if the next scheduled dose is more than 6 hours away. A missed dose of trametinib in the combination is taken only if the next scheduled dose is more than 12 hours away. If vomiting follows a Finlee dose, no extra dose is given and the next dose is taken at the scheduled time.

Method of Administration

• Tafinlar capsules are swallowed whole with water. They must not be chewed or opened, or mixed with food or liquids, because dabrafenib is chemically unstable in them.
• Doses are taken at similar times each day, about 12 hours apart. When the combination is used, the once-daily trametinib dose is taken at the same time each day with either the morning or the evening dose of dabrafenib.
• Take dabrafenib at least 1 hour before or at least 2 hours after a meal.

Combination With Trametinib

When dabrafenib is given with trametinib, the trametinib SmPC must be consulted before treatment starts. Warnings on haemorrhage, reduced ejection fraction, liver events, hypertension, interstitial lung disease, rash, rhabdomyolysis and gastrointestinal events are set out there in full.

BRAF Testing and Previous BRAF Inhibitor Treatment

Efficacy and safety have not been established in wild-type BRAF melanoma, lung cancer or thyroid cancer, so dabrafenib is not used in them. Data are limited in patients whose melanoma progressed on a BRAF inhibitor: the combination is less effective there, so other options should be considered first, and the sequence of treatments after BRAF inhibitor progression has not been established.

New Malignancies

• Cutaneous squamous cell carcinoma (including keratoacanthoma): occurred in 10% (22/211) of patients on dabrafenib alone and 18% (63/349) on vemurafenib in two Phase III melanoma studies, and in about 2% on the combination in the pivotal melanoma and lung studies. In the adjuvant melanoma study it occurred in 1% (6/435) on the combination and 1% (5/432) on placebo. In one melanoma study the median time to the first case was 223 days on the combination and 60 days on dabrafenib alone. The skin is examined before starting, monthly during treatment and for up to 6 months afterwards, or until another anticancer therapy starts. Cases are removed by dermatological excision, and treatment continues without dose adjustment. Patients should report new skin lesions immediately.
• New primary melanoma: reported within the first 5 months of dabrafenib alone in melanoma studies. It is managed by excision without any change to treatment, with skin monitoring as above.
• Non-cutaneous malignancies: in laboratory studies BRAF inhibitors activate MAP kinase signalling in BRAF wild-type cells that carry RAS mutations, which may raise the risk of non-cutaneous cancers. RAS-associated cancers have been reported with another BRAF inhibitor (chronic myelomonocytic leukaemia, non-cutaneous squamous cell carcinoma of the head and neck), with dabrafenib alone (pancreatic and bile duct adenocarcinoma) and with the combination (colorectal and pancreatic cancer). Before treatment, patients have a head and neck examination (at least inspection of the oral mucosa and palpation of lymph nodes) and a chest and abdomen CT scan. During treatment, monitoring may include a head and neck examination every 3 months and a chest and abdomen CT every 6 months. Anal and pelvic examinations are recommended before and at the end of treatment or when clinically indicated, with blood counts and chemistry as indicated. Benefit and risk are weighed in patients with a previous or concurrent cancer associated with RAS mutations. Monitoring continues for up to 6 months after stopping, or until another anticancer therapy starts.

Pyrexia

Fever occurs with dabrafenib alone and more often and more severely with the combination. In one melanoma study it was reported in 57% of patients on the combination (7% grade 3) and 33% on dabrafenib alone (2% grade 3). In the adjuvant melanoma study it occurred in 67% on the combination (6% grade 3 or 4) against 15% on placebo. About half of the first episodes occur in the first month, and about a third of patients have three or more episodes. Serious non-infectious febrile events (fever with severe rigors, dehydration, hypotension and/or pre-renal acute renal insufficiency) occurred in 1% of patients on dabrafenib alone.

Therapy (dabrafenib alone, or both medicines in the combination) is interrupted when the temperature reaches 38 °C or higher, and after a recurrence it can be interrupted at the first symptom. An antipyretic such as ibuprofen or paracetamol is started, oral corticosteroids are considered if antipyretics are not enough, and the patient is checked for signs of infection. Treatment restarts when the fever has resolved, at a reduced dose if the fever came with other severe signs or symptoms.

Bleeding, Eyes, Heart, Blood Pressure and Liver

• Haemorrhage: major and fatal haemorrhages have occurred with the combination.
• Eyes: uveitis, iridocyclitis and iritis have been reported with dabrafenib alone and with the combination. Patients are monitored routinely for changes in vision, photophobia and eye pain. Cases suggestive of Vogt-Koyanagi-Harada syndrome (bilateral panuveitis or iridocyclitis) have been reported with the combination: dabrafenib is withheld until the inflammation resolves, an ophthalmologist may be consulted, and systemic corticosteroids may be needed. Retinal pigment epithelial detachment and retinal vein occlusion can occur with the combination (see the trametinib SmPC), and no change in the dabrafenib dose is needed for them.
• Heart: the left ventricular ejection fraction fell in 8% of patients on the combination, mostly with symptoms and reversibly. Patients with an ejection fraction below the lower limit of normal were not studied, so the combination is used with caution in conditions that may impair left ventricular function.
• Blood pressure: raised blood pressure has occurred with or without existing hypertension. It is measured at the start and during treatment and treated with standard therapy as needed.
• Liver: hepatic adverse events have been reported with the combination. Liver function is checked every four weeks for 6 months after starting trametinib, and thereafter as clinically indicated.

Kidney, Pancreas, Clots and Other Reactions

• Renal failure: reported in under 1% of patients on dabrafenib alone and 1% on the combination, usually with fever and dehydration, and granulomatous nephritis has been reported. Serum creatinine is monitored. Dabrafenib has not been studied with creatinine above 1.5 times the upper limit of normal, so caution is needed there.
• Pancreatitis: reported in under 1% of melanoma patients and in about 4% in the lung cancer study on the combination. Unexplained abdominal pain needs prompt investigation including serum amylase and lipase, and patients are monitored closely if treatment restarts after an episode.
• Deep vein thrombosis and pulmonary embolism: can occur with the combination. Patients with shortness of breath, chest pain, or arm or leg swelling should seek care at once. Both medicines are stopped permanently for life-threatening pulmonary embolism.
• Severe cutaneous adverse reactions: Stevens-Johnson syndrome and DRESS, which can be life-threatening or fatal, have been reported with the combination. Patients are told the signs before starting, and both medicines are withdrawn if they appear.
• Colitis and gastrointestinal perforation: reported with the combination, including fatal cases.
• Interstitial lung disease: dabrafenib may continue at the same dose when the combination is used (see the trametinib SmPC).
• Sarcoidosis: reported with the combination, mostly in the skin, lung, eye and lymph nodes. It should not be mistaken for disease progression.
• Haemophagocytic lymphohistiocytosis: seen after marketing. If confirmed, both medicines are discontinued and the condition is treated.
• Tumour lysis syndrome: can be fatal. Risk factors are a high tumour burden, chronic renal insufficiency, oliguria, dehydration, hypotension and acidic urine. Patients at risk are monitored closely and prophylactic hydration is considered.
• Radiation: radiation recall and radiation sensitisation, mostly of the skin but also including the spinal cord, have been reported before, during or after radiotherapy.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential must use effective contraception during treatment and for 2 weeks after stopping dabrafenib, and for 16 weeks after the last dose of trametinib when it is combined with dabrafenib. Because dabrafenib may reduce the efficacy of hormonal contraceptives, an effective alternative method is needed.
• Pregnancy: there are no data in pregnant women. Animal studies showed reproductive toxicity and embryo-foetal developmental toxicity, including teratogenic effects. Dabrafenib is not given to pregnant women unless the benefit to the mother outweighs the possible risk to the foetus, and a woman who becomes pregnant is told of the hazard to the foetus.
• Breastfeeding: it is not known whether dabrafenib passes into human milk, and a risk to the breastfed child cannot be excluded. A decision is made whether to stop breastfeeding or dabrafenib.
• Fertility: there are no human data. Dabrafenib may impair male and female fertility, because adverse effects on the reproductive organs were seen in animals.

Effect on Driving

Dabrafenib has a minor influence on the ability to drive and use machines. Patients should be aware that fatigue and eye problems can affect tasks that require judgement, motor or cognitive skills.

Tafinlar capsules need no special storage conditions. They are supplied in an opaque white high-density polyethylene bottle with a polypropylene screw cap and a silica gel desiccant; each bottle holds 28 or 120 capsules (not all pack sizes may be marketed).

Finlee dispersible tablets need no special temperature storage conditions. Keep them in the original package to protect from moisture. No cold chain is required for either product.

Tafinlar capsules: 3 years. Finlee dispersible tablets: 2 years. Finlee tablet suspension: use within 30 minutes of preparation.

Prescription only (Rx), on the prescription of a physician experienced in the use of anti-cancer medicinal products, after the tumour’s BRAF mutation has been confirmed. Tafinlar capsules and Finlee tablets are taken at home, so they are supplied to the patient or to the treating clinic on prescription.