Regorafenib

Regorafenib is an oral inhibitor of several membrane-bound and intracellular protein kinases that take part in normal cell function and in tumour growth, angiogenesis and maintenance of the tumour microenvironment. Its two main circulating metabolites, M-2 and M-5, are also active and have similar potency.

Mechanism of Action

• Angiogenesis: regorafenib blocks VEGFR1, VEGFR2, VEGFR3 and TIE2, kinases that drive the formation of tumour blood vessels.
• Oncogenic kinases: it inhibits KIT, RET, RAF-1, BRAF and the mutant BRAF V600E. In particular it inhibits mutated KIT, a major oncogenic driver in gastrointestinal stromal tumours, and thereby blocks tumour cell proliferation.
• Metastasis and tumour immunity: it also inhibits VEGFR3, PDGFR and FGFR (metastasis) and CSF1R (tumour immunity). In preclinical work it reduced the number of tumour-associated macrophages and showed anti-metastatic effects in vivo.
• Further kinases in vitro: DrugBank also lists PDGFR-alpha and -beta, FGFR1 and FGFR2, DDR2, TrkA, Eph2A, SAPK2, PTK5 and Abl, inhibited at concentrations reached in patients.
• Preclinical activity: broad antitumour activity in colorectal, gastrointestinal stromal and hepatocellular tumour models, probably through anti-angiogenic and anti-proliferative effects.
• Active metabolites: M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl) reach steady-state concentrations similar to regorafenib and showed similar efficacy in vitro and in vivo.

Pharmacokinetics

• Absorption: after a single 160 mg dose (four 40 mg tablets), mean peak plasma levels of about 2.5 mg/L are reached after about 3 to 4 hours. Relative to an oral solution, the average bioavailability of the tablets was 69% (60 mg) and 83% (100 mg). Regorafenib exposure was 48% higher with a high-fat breakfast and 36% higher with a low-fat breakfast than when fasting. Levels of M-2 and M-5 are highest after a low-fat breakfast, which is why the tablets are taken after a light, low-fat meal.
• Distribution: plasma concentration–time profiles show several peaks across the 24-hour interval because of enterohepatic circulation. Protein binding is high: 99.5% for regorafenib, 99.8% for M-2 and 99.95% for M-5. M-2 and M-5 are weak P-gp substrates, and M-5 is a weak BCRP substrate.
• Metabolism: mainly hepatic, by CYP3A4 (oxidation) and UGT1A9 (glucuronidation). Two major and six minor metabolites occur in plasma. M-2 is further metabolised by CYP3A4 and UGT1A9. Gut bacteria can reduce or hydrolyse metabolites, allowing reabsorption of the unconjugated drug and metabolites.
• Elimination: the mean half-life of regorafenib and M-2 in plasma ranges from 20 to 30 hours in different studies; M-5 has a longer half-life. After a radiolabelled 120 mg oral solution, about 71% of the dose was excreted in faeces within 12 days (47% as unchanged regorafenib, 24% as metabolites) and about 19% in urine (17% as glucuronides).
• Special populations: exposure to regorafenib, M-2 and M-5 is similar in mild, moderate and severe renal impairment and in normal renal function. No relevant differences were seen with mild hepatic impairment (Child-Pugh A); data are limited in moderate impairment (Child-Pugh B) and the medicine has not been studied in severe impairment. Age and sex made no relevant difference to exposure, safety or efficacy.

Regorafenib is used as monotherapy in adults with:

• Metastatic colorectal cancer (CRC): patients previously treated with, or not considered candidates for, available therapies, which include fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy.
• Gastrointestinal stromal tumours (GIST): unresectable or metastatic GIST that progressed on, or is intolerant to, prior treatment with imatinib and sunitinib.
• Hepatocellular carcinoma (HCC): patients previously treated with sorafenib.

• Hypersensitivity to regorafenib or to any of the excipients (see Composition).

The safety profile rests on more than 4,800 patients treated in clinical trials, including placebo-controlled phase III data for 636 patients with metastatic CRC, 132 with GIST and 374 with HCC, and is consistent with a phase IIIb study of 2,872 patients with metastatic CRC. The most serious reactions are severe liver injury, haemorrhage, gastrointestinal perforation and infection. The most frequent (30% or more) are pain, hand-foot skin reaction, asthenia or fatigue, diarrhoea, decreased appetite and food intake, hypertension and infection.

Very common (≥1/10): infection, thrombocytopenia, anaemia, decreased appetite and food intake, haemorrhage, hypertension, dysphonia, diarrhoea, stomatitis, vomiting, nausea, constipation, hyperbilirubinaemia, raised transaminases, hand-foot skin reaction (palmar-plantar erythrodysaesthesia syndrome), rash, asthenia or fatigue, pain, fever, mucosal inflammation, weight loss.

Common (≥1/100 to <1/10): leucopenia, hypothyroidism, hypokalaemia, hypophosphataemia, hypocalcaemia, hyponatraemia, hypomagnesaemia, hyperuricaemia, dehydration, headache, tremor, peripheral neuropathy, taste disorders, dry mouth, gastro-oesophageal reflux, gastroenteritis, alopecia, dry skin, exfoliative rash, muscle spasms, proteinuria, raised amylase and lipase, abnormal INR.

Uncommon (≥1/1,000 to <1/100): hypersensitivity reaction, myocardial infarction, myocardial ischaemia, hypertensive crisis, gastrointestinal perforation, gastrointestinal fistula, pancreatitis, severe liver injury (including liver failure), nail disorder, erythema multiforme.

Rare (≥1/10,000 to <1/1,000): keratoacanthoma or squamous cell carcinoma of the skin, thrombotic microangiopathy, posterior reversible encephalopathy syndrome, Stevens–Johnson syndrome, toxic epidermal necrolysis.

Not known: hyperammonaemic encephalopathy, arterial aneurysms and dissections.

Fatal cases have been reported with infection, haemorrhage, gastrointestinal perforation and severe liver injury. The types of pain reported most often (10% or more) were abdominal pain and back pain.

Regorafenib is metabolised by CYP3A4 and UGT1A9, so strong inhibitors and inducers of these enzymes call for attention.

• Strong CYP3A4 inhibitors: ketoconazole 400 mg for 18 days raised the AUC of a single 160 mg dose of regorafenib by about 33% and lowered the AUC of the active metabolites M-2 and M-5 by about 90%. Concomitant use of strong CYP3A4 inhibitors (for example clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin, voriconazole) should be avoided, because their effect on steady-state exposure has not been studied.
• Strong UGT1A9 inhibitors (for example mefenamic acid, diflunisal, niflumic acid): avoid, for the same reason.
• Strong CYP3A4 inducers: rifampicin 600 mg for 9 days lowered the AUC of regorafenib by about 50%, raised exposure to M-5 3- to 4-fold and left M-2 unchanged. Other strong inducers (for example phenytoin, carbamazepine, phenobarbital, St John’s wort) may also increase regorafenib metabolism. They should be avoided, or an alternative with no or minimal CYP3A4-inducing potential chosen.
• Anticoagulants and other medicines that raise bleeding risk (for example warfarin, phenprocoumon): blood counts and coagulation parameters should be monitored.
• UGT1A1 and other substrates: regorafenib inhibits UGT1A1 (mild indirect hyperbilirubinaemia may occur in Gilbert’s syndrome) and, according to DrugBank, P-glycoprotein. Exposure to medicines cleared by these routes may rise; section 4.5 of the SmPC gives further advice on specific substrates.
• Food: take after a light, low-fat meal. Avoid grapefruit products (they inhibit CYP3A4) and St John’s wort (it induces CYP3A4).

Treatment should be prescribed by physicians experienced in the administration of anticancer therapy. Regorafenib is taken by mouth at the same time each day. The tablets are swallowed whole with water after a light meal containing less than 30% fat. An example is one portion of cereal (about 30 g), a glass of skimmed milk, a slice of toast with jam, a glass of apple juice and a cup of coffee or tea (520 calories, 2 g fat).

Recommended Dose

• 160 mg (four 40 mg tablets) once daily for 3 weeks, followed by 1 week off treatment. This 4-week period is one treatment cycle.
• Treatment continues as long as benefit is seen or until unacceptable toxicity occurs.
• Patients with performance status 2 or higher were excluded from clinical studies, so data in them are limited.

Dose Adjustments

Doses are changed in 40 mg (one tablet) steps. The lowest recommended daily dose is 80 mg and the maximum is 160 mg.

• Hand-foot skin reaction (HFSR), grade 1: keep the dose and start supportive measures for symptom relief.
• HFSR, grade 2: first occurrence, reduce by 40 mg and start supportive measures; if there is no improvement despite the reduction, interrupt for at least 7 days until grade 0 or 1. With no improvement within 7 days, or on a second occurrence, interrupt until grade 0 or 1 and restart 40 mg lower. On a third occurrence, interrupt until grade 0 or 1 and restart 40 mg lower. A fourth occurrence means stopping permanently. Re-escalation is permitted at the physician’s discretion.
• HFSR, grade 3: first or second occurrence, start supportive measures at once, interrupt for at least 7 days until grade 0 or 1, and restart 40 mg lower (re-escalation permitted at the physician’s discretion). A third occurrence means stopping permanently.
• Liver tests, ALT or AST up to 5 times the upper limit of normal (ULN; maximum grade 2): continue treatment and monitor liver function weekly until transaminases return below 3 times ULN (grade 1) or to baseline.
• Liver tests, above 5 and up to 20 times ULN (grade 3): on the first occurrence, interrupt and monitor weekly until below 3 times ULN or baseline. Restart only if the potential benefit outweighs the risk of hepatotoxicity, at a dose reduced by 40 mg, with weekly liver monitoring for at least 4 weeks. If it recurs, stop permanently.
• Liver tests, above 20 times ULN (grade 4): stop permanently.
• Liver tests, above 3 times ULN (grade 2 or higher) with bilirubin above 2 times ULN: stop permanently and monitor weekly until resolution or return to baseline. Patients with Gilbert’s syndrome who develop raised transaminases are managed according to the recommendation for the observed ALT or AST elevation.
• Hypertension and laboratory abnormalities: for severe or persistent hypertension despite adequate treatment, interrupt temporarily and/or reduce the dose at the physician’s discretion, and stop for hypertensive crisis. For persistent or recurrent significant laboratory abnormalities, interruption, reduction or permanent discontinuation should be considered.

Special Populations

• Hepatic impairment: no adjustment in mild impairment (Child-Pugh A). In moderate impairment (Child-Pugh B) data are limited, so no dose recommendation can be made and overall safety is monitored closely. Not recommended in severe impairment (Child-Pugh C), which has not been studied.
• Renal impairment: no dose adjustment in mild, moderate or severe impairment.
• Elderly: no relevant differences in exposure, safety or efficacy compared with younger patients (aged under 65).
• Sex: no dose adjustment is needed.
• Ethnic origin: no dose adjustment is needed, but HFSR, severe liver test abnormalities and hepatic dysfunction were more frequent in Asian (in particular Japanese) patients than in Caucasians. Data in black patients are limited.
• Children and adolescents: there is no relevant use in these indications, and safety and efficacy under 18 years have not been established.

Missed or Vomited Dose

If a dose is missed, it is taken on the same day as soon as the patient remembers. Two doses are not taken on the same day to make up for a missed one. If vomiting follows a dose, no additional tablets are taken.

Liver Function Monitoring

Abnormal liver function tests (ALT, AST, bilirubin) are frequent with regorafenib. Severe (grade 3 or 4) abnormalities and hepatic dysfunction with clinical signs, including hepatic failure and fatal outcomes, have been reported in a small proportion of patients, and they were more frequent in Asian (in particular Japanese) patients than in Caucasians.

• Before treatment: liver function tests (ALT, AST and bilirubin) are performed.
• First 2 months: liver function is monitored closely, at least every 2 weeks.
• Afterwards: monitoring continues periodically, at least monthly and as clinically indicated.
• If tests worsen: when the worsening is considered related to regorafenib (no alternative cause such as post-hepatic cholestasis or disease progression), follow the dose-modification and monitoring rules in Dose Adjustments: continue with weekly checks, interrupt, reduce or stop permanently, depending on the size of the rise.
• Gilbert’s syndrome: regorafenib inhibits UGT1A1, so mild indirect (unconjugated) hyperbilirubinaemia may occur.
• Hepatic impairment: regorafenib is eliminated mainly by the liver. Overall safety is monitored closely in mild or moderate impairment, and it is not recommended in severe impairment (Child-Pugh C), where exposure might be increased.

Infections

Infection events were more frequent and some were fatal. Interrupting regorafenib should be considered if an infection worsens.

Haemorrhage

Haemorrhagic events were more frequent, and some were fatal. Blood counts and coagulation parameters are monitored in patients predisposed to bleeding and in those taking anticoagulants (for example warfarin or phenprocoumon) or other medicines that raise bleeding risk. In liver cirrhosis, oesophageal varices should be screened for and treated according to standard care before starting. In severe bleeding needing urgent medical intervention, permanent discontinuation should be considered.

Gastrointestinal Perforation and Fistula

Perforation (including fatal cases) and fistulae have been reported. They are also common complications of intra-abdominal cancer. Regorafenib should be stopped in patients who develop perforation or fistula.

Cardiac Ischaemia and Infarction

Myocardial ischaemia and infarction were more frequent. Patients with unstable or new-onset angina (within 3 months of starting), recent myocardial infarction (within 6 months) or NYHA class 2 or higher heart failure were excluded from the studies. Patients with ischaemic heart disease are monitored for signs and symptoms of myocardial ischaemia. If ischaemia or infarction occurs, regorafenib is interrupted until it resolves, and restarting depends on the benefit and risk for the patient; it is stopped permanently if there is no resolution.

Hypertension

Arterial hypertension was more frequent. Blood pressure should be controlled before starting, then monitored and treated according to standard practice. For severe or persistent hypertension, treatment may be interrupted and/or the dose reduced; it is stopped in hypertensive crisis.

Aneurysms and Artery Dissections

Inhibitors of the VEGF pathway, in patients with or without hypertension, may promote aneurysms and artery dissections. This risk should be weighed carefully before starting, particularly with risk factors such as hypertension or a history of aneurysm.

Hyperammonaemic Encephalopathy, PRES and Thrombotic Microangiopathy

• Hyperammonaemic encephalopathy: seen with regorafenib, including fatal cases. In patients with unexplained lethargy or a change in mental status, ammonia levels should be measured; if confirmed, permanent discontinuation should be considered.
• Posterior reversible encephalopathy syndrome (PRES): signs include seizures, headache, altered mental status and visual disturbance or cortical blindness, with or without hypertension; brain imaging confirms it. Regorafenib is stopped, with control of hypertension and supportive care.
• Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura, should be considered with haemolytic anaemia, thrombocytopenia, fatigue, fluctuating neurological signs, renal impairment and fever. Regorafenib is stopped and prompt treatment is needed; the effects reversed after stopping.

Wound Healing

Medicines with anti-angiogenic properties may interfere with wound healing. Regorafenib is interrupted temporarily as a precaution in patients having major surgery, and resumption depends on clinical judgement of adequate wound healing.

Skin Reactions

Hand-foot skin reaction (palmar-plantar erythrodysaesthesia) and rash are the most frequent skin reactions, and HFSR was more frequent in Asian (in particular Japanese) patients. Prevention includes control of calluses and shoe cushions and gloves to prevent pressure on soles and palms. Management may include keratolytic creams (for example urea-, salicylic acid- or alpha-hydroxy acid-based, applied sparingly to affected areas only) and moisturising creams (applied liberally). Dose reduction or temporary interruption, or permanent discontinuation in severe or persistent cases, should be considered.

Laboratory Abnormalities

Electrolyte abnormalities (hypophosphataemia, hypocalcaemia, hyponatraemia, hypokalaemia) and metabolic abnormalities (increases in thyroid-stimulating hormone, lipase and amylase) were more frequent. They are generally mild to moderate, without clinical signs, and usually do not need dose interruption or reduction. Biochemical and metabolic parameters are monitored, with replacement therapy according to standard practice if needed.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential must be told that regorafenib may cause foetal harm. Women of childbearing potential and men should use effective contraception during treatment and for up to 8 weeks after it ends.
• Pregnancy: there are no data in pregnant women. Regorafenib is suspected to cause foetal harm because of its mechanism of action, and animal studies showed reproductive toxicity. It should not be used in pregnancy unless clearly necessary, after careful weighing of the benefit to the mother and the risk to the foetus.
• Breastfeeding: it is unknown whether regorafenib or its metabolites pass into human milk; they do in rats. A risk to the breastfed child cannot be excluded, and regorafenib could harm infant growth and development. Breastfeeding must be stopped during treatment.
• Fertility: there are no human data. Animal studies indicate that regorafenib can impair male and female fertility.

Sodium and Soya Lecithin

A daily dose of 160 mg contains 56.06 mg of sodium, equal to 3% of the WHO recommended maximum daily intake of 2 g for an adult. It also contains 1.68 mg of lecithin derived from soya. Hypersensitivity to any excipient is a contraindication.

Effect on Driving

No studies on the ability to drive or use machines have been done. Patients with symptoms that affect concentration and reaction should not drive or use machines until the effect subsides.

Store Stivarga in the original package to protect it from moisture, and keep the bottle tightly closed. The bottle is white opaque polyethylene with a polypropylene screw cap and contains a molecular sieve desiccant. It holds 28 tablets, in packs of 28 or 84 (3 bottles of 28); not all pack sizes may be marketed. The SmPC sets no special temperature requirement. Once opened, use the tablets within 7 weeks (see Shelf Life). Keep out of the sight and reach of children.

3 years unopened. Once the bottle is opened, the tablets are stable for 7 weeks; after that, discard them. Do not use after the expiry date on the pack.

Prescription only (Rx), subject to restricted medical prescription (Annex II B), on the prescription of a specialist experienced in anticancer therapy. The prescriber checks liver function before treatment and monitors it closely, at least every 2 weeks for the first 2 months and then at least monthly (see Special Instructions). Regorafenib is taken at home, so it is supplied to the patient or to the treating clinic on prescription.