Vemurafenib

Vemurafenib is an inhibitor of the BRAF serine-threonine kinase. Mutations in the BRAF gene make the BRAF protein constitutively active, which can drive cell proliferation without growth factors. Vemurafenib potently inhibits BRAF kinases that carry activating mutations at codon 600 (V600), so it is used only when the tumour carries such a mutation.

Mechanism of Action

• Inhibition: a competitive inhibitor of mutated BRAF, especially potent against V600E. In biochemical assays the IC50 was 7 to 14 nM for kinases carrying V600E, V600K, V600R, V600D, V600G, V600M or V600A, against 39 nM for wild-type BRAF. V600E is estimated to account for 87.3% of V600 mutations in melanoma and V600K for 7.9%.
• Pathway effects: the inhibition was confirmed in ERK phosphorylation and cell-proliferation assays in melanoma cell lines with V600-mutant BRAF. In patients, treatment lowered phosphorylated ERK and the proliferation marker Ki-67, consistent with a near-complete block of the MAPK pathway.
• Limits of use: it should not be used in melanoma with wild-type BRAF, and efficacy and safety have not been convincingly established for rare V600 mutations other than V600E and V600K.

Pharmacokinetics

• Absorption: a Class IV substance in the Biopharmaceutics Classification System (low solubility and permeability), with high variability between patients. The median time to peak is about 4 hours after a single 960 mg dose. Bioavailability at steady state relative to an intravenous microdose averaged 64% (range 32–115%, four patients). Exposure accumulates on twice-daily dosing: by day 15, AUC was 15- to 17-fold and Cmax 13- to 14-fold the day 1 values.
• Food: a high-fat meal raised exposure to a single 960 mg dose (Cmax 2.5-fold, AUC 4.6- to 5.1-fold) and delayed the median time to peak from 4 to 7.5 hours. The effect at steady state is unknown; consistent intake on an empty stomach may give significantly lower steady-state exposure than intake with or shortly after a meal.
• Distribution: apparent volume of distribution about 91 L (population estimate); more than 99% bound to plasma proteins in vitro.
• Metabolism: CYP3A4 is the main enzyme in vitro, and glucuronidation and glycosylation conjugates were also found. The parent compound made up 95% of the material in plasma.
• Elimination: apparent clearance 29.3 L/day and population elimination half-life 51.6 hours (individual estimates 29.8–119.5 hours). About 95% of a radiolabelled dose was recovered within 18 days, 94% in faeces and under 1% in urine; biliary excretion of unchanged drug may be an important route.
• Special populations: age had no significant effect. Apparent clearance was 17% higher and the volume of distribution 48% higher in men than in women, too little to need a dose change. Mild or moderate renal impairment (creatinine clearance above 40 mL/min) and AST or ALT up to 3 times the upper limit of normal did not change clearance. There are no data in severe renal impairment, and too few to judge other degrees of hepatic impairment.

• Melanoma: as monotherapy in adults with BRAF V600 mutation-positive unresectable or metastatic melanoma.
• The BRAF V600 mutation status of the tumour must be confirmed by a validated test before treatment.

• Hypersensitivity to vemurafenib or to any of the excipients.

Reactions of any grade in more than 30% of patients were arthralgia, fatigue, rash, photosensitivity reaction, alopecia, nausea, diarrhoea, headache, pruritus, vomiting, skin papilloma and hyperkeratosis. The most common grade 3 reactions (5% or more) were cutaneous squamous cell carcinoma (cuSCC), keratoacanthoma, rash, arthralgia and increased gamma-glutamyltransferase (GGT); cuSCC was usually treated by local excision. The frequencies below come from 468 patients in a phase III and a phase II study in BRAF V600 mutation-positive melanoma, plus events from all trials and post-marketing reports.

Very common (≥1/10): cutaneous squamous cell carcinoma, keratoacanthoma, seborrhoeic keratosis, skin papilloma, decreased appetite, headache, dysgeusia, dizziness, cough, diarrhoea, vomiting, nausea, constipation, photosensitivity reaction, actinic keratosis, rash, maculopapular rash, pruritus, hyperkeratosis, erythema, palmar-plantar erythrodysaesthesia syndrome, alopecia, dry skin, sunburn, arthralgia, myalgia, pain in extremity, musculoskeletal pain, back pain, fatigue, pyrexia, peripheral oedema, asthenia.

Common (≥1/100 to <1/10): folliculitis, basal cell carcinoma, new primary melanoma, neutropenia, thrombocytopenia, facial (seventh) nerve paralysis, peripheral neuropathy, uveitis, vasculitis, stomatitis, papular rash, panniculitis (including erythema nodosum), keratosis pilaris, arthritis, increased ALT, alkaline phosphatase, AST, bilirubin and GGT, weight decreased, QT prolongation on the ECG, increased blood creatinine, potentiation of radiation toxicity.

Uncommon (≥1/1,000 to <1/100): non-cutaneous squamous cell carcinoma, retinal vein occlusion, iridocyclitis, pancreatitis, liver injury, toxic epidermal necrolysis, Stevens-Johnson syndrome, plantar fascial fibromatosis, Dupuytren’s contracture.

Rare (≥1/10,000 to <1/1,000): chronic myelomonocytic leukaemia (progression of an existing NRAS-mutated disease), pancreatic adenocarcinoma (progression of an existing KRAS-mutated cancer), sarcoidosis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute interstitial nephritis, acute tubular necrosis.

Important serious reactions are new skin and other malignancies, serious hypersensitivity including anaphylaxis, severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS), QT prolongation, liver injury, pancreatitis, uveitis, iritis and retinal vein occlusion, kidney injury, and radiation recall or sensitisation (some visceral cases were fatal).

Vemurafenib is metabolised mainly by CYP3A4 and is a substrate of P-gp and BCRP. It is also a moderate CYP1A2 inhibitor, a CYP3A4 inducer and an inhibitor of P-gp and BCRP, so it can change the levels of other medicines.

• CYP1A2 substrates: use with narrow-window substrates (for example agomelatine, alosetron, duloxetine, melatonin, ramelteon, tacrine, tizanidine, theophylline) is not recommended; if unavoidable, take care and consider a lower dose of the other medicine. Caffeine exposure rose 2.6-fold and tizanidine AUC 4.7-fold, so caffeine intake should be limited.
• CYP3A4 substrates: exposure (AUC) to a CYP3A4 probe substrate fell by 39% on average (up to 80%). Narrow-window CYP3A4 substrates are not recommended because their effect may be reduced, and contraceptive pills metabolised by CYP3A4 may be less effective.
• Warfarin and CYP2C8: S-warfarin exposure rose by 18%, so take care and consider extra INR monitoring. CYP2C8 was moderately inhibited in vitro; use caution with narrow-window CYP2C8 substrates.
• P-gp and BCRP substrates: digoxin AUC rose about 1.8-fold and Cmax 1.5-fold. Take care with P-gp substrates (such as digoxin, dabigatran etexilate, aliskiren), consider a lower dose, and consider drug-level monitoring for those with a narrow therapeutic index. Exposure to BCRP substrates (such as methotrexate, mitoxantrone, rosuvastatin) may also rise.
• Strong CYP3A4/P-gp inhibitors: itraconazole raised vemurafenib exposure (AUC) by about 40%. Use with caution with strong inhibitors of CYP3A4, glucuronidation or transport proteins (ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone, atazanavir), monitor safety and adjust the dose if indicated.
• Strong inducers: rifampicin lowered vemurafenib exposure by about 40%. Avoid strong inducers of CYP3A4, P-gp or glucuronidation where possible (rifampicin, rifabutin, carbamazepine, phenytoin, St John’s wort).
• Ipilimumab: asymptomatic grade 3 rises in transaminases and bilirubin occurred when the two were given together in a phase I trial; concurrent use is not recommended.
• QT-prolonging medicines and radiotherapy: not recommended with medicines known to prolong the QT interval; radiation toxicity can be potentiated (see Special Instructions).
• Timing and grapefruit: because of the long half-life, the full effect on another medicine may not appear until about 8 days of treatment, and about 8 days of washout may be needed after stopping. Grapefruit products inhibit CYP3A4 and may raise vemurafenib levels; use caution.

Treatment must be started and supervised by a qualified physician experienced in the use of anticancer medicinal products, after the tumour has been confirmed BRAF V600 mutation-positive by a validated test. The tablets are swallowed whole with water and must not be chewed or crushed.

Recommended Dose

• 960 mg (four 240 mg tablets) twice daily, a total of 1,920 mg a day, with or without food; taking both daily doses consistently on an empty stomach should be avoided.
• Treatment continues until disease progression or unacceptable toxicity.

Dose Adjustments for Side Effects

• Reactions or QTc prolongation may need a dose reduction, interruption or discontinuation; doses below 480 mg twice daily are not recommended. If cutaneous squamous cell carcinoma develops, continue at the same dose.
• Grade 1 or tolerable Grade 2: keep 960 mg twice daily.
• Intolerable Grade 2 or Grade 3: first occurrence, interrupt until Grade 0–1 and resume at 720 mg twice daily (480 mg twice daily if already reduced). Second occurrence or persistence after interruption, interrupt until Grade 0–1 and resume at 480 mg twice daily (stop permanently if already at 480 mg). Third occurrence or persistence after the second reduction, stop permanently.
• Grade 4: first occurrence, stop permanently or interrupt until Grade 0–1 and resume at 480 mg twice daily (stop permanently if already at 480 mg).
• QTc prolongation: the SmPC gives a separate schedule (its table 2); the principles are under Special Instructions.

Special Populations

• Elderly: no special dose adjustment above 65 years of age.
• Renal impairment: no adjustment of the starting dose in mild or moderate impairment; data in severe impairment are limited, so use with caution and monitor closely.
• Hepatic impairment: no adjustment of the starting dose. Data in moderate to severe impairment are limited and exposure may be higher, so monitor closely, especially after the first weeks, with an ECG every month for the first 3 months.
• Children and adolescents: safety and efficacy below 18 years have not been established; no dose recommendation can be made.
• Non-Caucasian patients: safety and efficacy have not been established; no data are available.

Missed or Vomited Dose

A missed dose can be taken up to 4 hours before the next one to keep the twice-daily schedule; never take both doses together. After vomiting, do not take an extra dose and carry on as usual.

Hypersensitivity and Severe Skin Reactions

Serious hypersensitivity reactions, including anaphylaxis, have been reported; severe ones can include Stevens-Johnson syndrome, generalised rash, erythema or hypotension. Severe dermatological reactions have also occurred, including rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis in the pivotal trial and, after marketing, DRESS. Treatment must be stopped permanently after a severe hypersensitivity or dermatological reaction.

Skin Cancers and Other Malignancies

• Cutaneous squamous cell carcinoma, including keratoacanthoma: every patient needs a dermatological evaluation before treatment and routine checks during it. The prescriber should examine the patient monthly during treatment and for up to 6 months after it (or until other anticancer treatment starts). Suspicious lesions are excised and sent for dermatopathology. Treatment continues without dose change, and patients should report any skin change.
• Non-cutaneous squamous cell carcinoma: a head and neck examination (at least inspection of the oral mucosa and palpation of lymph nodes) before treatment and every 3 months, and a chest CT scan before treatment and every 6 months. Anal and, for women, pelvic examinations are advised before and at the end of treatment or when clinically indicated. Follow-up continues for up to 6 months after stopping.
• New primary melanoma: reported in trials; managed by excision with treatment continued at the same dose, and monitored like cutaneous squamous cell carcinoma.
• Other cancers: by its mechanism, vemurafenib may promote progression of cancers associated with RAS mutations; weigh benefit and risk in patients with a current or earlier cancer of this kind.

QT Prolongation

Exposure-dependent QT prolongation was seen in an uncontrolled phase II study and can raise the risk of ventricular arrhythmias, including torsade de pointes. Treatment is not recommended with uncorrectable electrolyte abnormalities (including magnesium), long QT syndrome or medicines known to prolong the QT interval, and should not be started when the QTc is above 500 ms. An ECG and electrolytes (including magnesium) must be checked before treatment, after one month and after any dose change; in moderate to severe hepatic impairment also monthly for the first 3 months, then every 3 months or more often if indicated. If the QTc exceeds 500 ms, treatment is interrupted, electrolyte abnormalities are corrected and cardiac risk factors (for example heart failure, bradyarrhythmias) are controlled; it restarts at a lower dose once the QTc is below 500 ms. It is stopped permanently if the QTc exceeds 500 ms and has also risen by more than 60 ms from the pre-treatment value.

Eyes, Liver, Pancreas and Kidneys

• Eyes: serious reactions including uveitis, iritis and retinal vein occlusion have been reported; monitor routinely.
• Liver injury: severe cases have been reported. Measure transaminases, alkaline phosphatase and bilirubin before treatment and monthly during it; manage abnormal results by dose reduction, interruption or discontinuation.
• Pancreatitis: investigate unexplained abdominal pain promptly (including serum amylase and lipase) and monitor closely if treatment restarts after an episode.
• Renal toxicity: ranges from raised creatinine to acute interstitial nephritis and acute tubular necrosis. Measure serum creatinine before treatment and as clinically indicated.

Radiation, Sun and Connective Tissue

• Radiation: radiation recall and radiation sensitisation were reported in patients irradiated before, during or after treatment; most were cutaneous, but some visceral cases were fatal. Use caution with concurrent or sequential radiotherapy.
• Photosensitivity: mild to severe. Avoid sun exposure, wear protective clothing and use a broad-spectrum UVA/UVB sunscreen and lip balm (Sun Protection Factor 30 or higher) outdoors; intolerable Grade 2 or worse needs a dose modification.
• Dupuytren’s contracture and plantar fascial fibromatosis: mostly mild to moderate, but severe, disabling cases occur; manage by dose reduction, interruption or discontinuation.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential must use effective contraception during treatment and for at least 6 months after it. Vemurafenib might reduce the efficacy of hormonal contraceptives.
• Pregnancy: there are no data in pregnant women. No teratogenicity was seen in rat or rabbit embryos or foetuses, but vemurafenib crossed the placenta in animals and, from its mechanism of action, could cause foetal harm. It should not be given in pregnancy unless the possible benefit to the mother outweighs the possible risk to the foetus.
• Breastfeeding: it is not known whether vemurafenib passes into human milk and a risk to the infant cannot be excluded. A decision must be made whether to stop breastfeeding or stop treatment, weighing the benefit of breastfeeding for the child against the benefit of therapy for the woman.
• Fertility: no specific fertility studies were done in animals; repeat-dose studies in rats and dogs showed no histopathological findings in the reproductive organs of either sex.

Effect on Driving

Vemurafenib has a minor influence on the ability to drive and use machines. Patients should be aware that fatigue or eye problems could be a reason not to drive.

Store Zelboraf tablets in the original package to protect them from moisture; the SmPC sets no temperature limit. They are supplied in aluminium/aluminium perforated unit-dose blisters, in packs of 56 film-coated tablets (7 blisters of 8 tablets). Keep out of the sight and reach of children.

3 years. Do not use after the expiry date on the pack.

Prescription only (Rx), under restricted medical prescription (Annex II B), with treatment started and supervised by a qualified physician experienced in the use of anticancer medicinal products. Zelboraf is taken at home, so it is supplied to the patient or the treating clinic on prescription.