Regorafenib: multikinase inhibitor (TKI) in mCRC, GIST, HCC
Regorafenib (brand name Stivarga) is an oral multikinase inhibitor that inhibits a wide range of tyrosine kinases involved in tumour growth, angiogenesis and immune modulation. Approved in the USA in 2012 and in the EU in 2013, regorafenib is used in pretreated metastatic colorectal cancer, gastrointestinal stromal tumours (GIST) and hepatocellular carcinoma (HCC).
Regorafenib is considered reserve therapy after failure of other systemic lines. Pivotal trials such as CORRECT (mCRC), GRID (GIST) and RESORCE (HCC) showed a moderate gain in overall survival, which must be balanced against the toxicity profile in everyday practice.
Mechanism of action
Regorafenib inhibits several kinase classes with different selectivity:
- Angiogenesis kinases: VEGFR1, 2, 3, TIE2
- Stromal kinases: PDGFR alpha and beta, FGFR1 and 2
- Oncogenic kinases: KIT, RET, RAF, BRAF
- Immunomodulatory kinases such as CSF1R
This multi-target activity inhibits tumour vessel formation, reduces stromal tumour support and exerts a direct antiproliferative effect on tumour cells with activated oncogenes such as KIT (in GIST) or RAF signalling pathways.
Regorafenib is metabolised hepatically via CYP3A4 to two active metabolites (M-2 and M-5) which also contribute to clinical efficacy.
Indications
- Metastatic colorectal cancer (mCRC): after failure of all established lines including fluoropyrimidines, oxaliplatin, irinotecan, anti-VEGF and anti-EGFR therapies
- Gastrointestinal stromal tumour (GIST): after failure of imatinib and sunitinib
- Hepatocellular carcinoma (HCC): after pretreatment with sorafenib
Regorafenib is not approved for first-line therapy and is not established in combination with chemotherapy.
Dosing and administration
Standard dose: 160 mg once daily (4 tablets of 40 mg) for 21 days, followed by a 7-day break. One cycle lasts 28 days.
Tablets are taken at the same time of day, preferably after a light low-fat meal (less than 600 kcal, less than 30 % fat). A high-fat meal can reduce bioavailability.
Dose modification: with relevant toxicity the dose is reduced stepwise to 120 mg, 80 mg or less. Some clinicians start with a dose escalation scheme (REDOS study) at 80 mg and increase weekly to reduce toxicity.
Visits: weekly for the first 2 months, later every 2 to 4 weeks, with assessment of skin reactions, blood count, liver values, blood pressure and clinical symptoms.
Side effects
Very common: hand-foot skin reaction (HFSR), diarrhoea, fatigue, anorexia, hypertension, mucositis, voice changes (dysphonia), raised liver transaminases, raised bilirubin, anaemia, thrombocytopenia.
Common: rash, pruritus, weight loss, nausea, vomiting, headache, tremor, fever, infections, proteinuria, hypothyroidism, wound healing disorders.
Uncommon and rare: hepatotoxic reactions up to liver failure, gastrointestinal perforation, fistula formation, severe bleeding, hypertensive crisis, posterior reversible encephalopathy syndrome (PRES), thromboembolic events.
Hand-foot skin reaction:
- Most common dose-limiting side effect; typically appears in the first 2 to 8 weeks
- Symptoms: painful redness, swelling, blisters, hyperkeratosis on hands and feet
- Prevention: comfortable soft shoes, avoid pressure points, pedicure before starting therapy, regular skin care with urea-containing creams
- Treatment: dose reduction or break, skin care products, topical steroids in severe cases
Hepatotoxicity: regular liver value checks at least every 2 weeks during the first 2 months; significant elevation calls for a break or therapy stop.
Interactions
- Strong CYP3A4 inhibitors (itraconazole, ketoconazole, clarithromycin, ritonavir): increased levels, dose reduction or avoid combination
- Strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St John's wort): falling levels, avoid combination if possible
- UGT1A1 or UGT1A9 substrates (irinotecan): risk of increased toxicity
- BCRP substrates (methotrexate, rosuvastatin): raised levels of co-medication
- Anticoagulants: increased bleeding risk, INR monitoring
- Live vaccines: contraindicated
Special considerations
Pregnancy: contraindicated. Reliable contraception during and at least 8 weeks after therapy for both sexes.
Breastfeeding: contraindicated.
Surgery: pause regorafenib at least 2 weeks before elective surgery due to wound healing disorders and bleeding risk. Restart after complete healing.
Hypertension: regular blood pressure monitoring, adjust antihypertensive therapy as needed.
Thyroid function: regular TSH monitoring; hypothyroidism is common and easily replaceable.
Patient communication: regorafenib treatment is demanding, especially in the first weeks. Honest counselling about possible skin reactions, fatigue and gastrointestinal complaints helps patients react early and not stop therapy on their own.
Quality of life: trial assessments show that, despite toxicity, quality of life is preserved in many patients, especially when side-effect management is consistent.
Related substances
- Sorafenib, predecessor TKI in HCC and RCC
- Sunitinib, another multikinase inhibitor
- Dasatinib, BCR-ABL and SRC inhibitor
- Fruquintinib, highly selective VEGFR TKI
- Sotorasib, KRAS G12C inhibitor
Frequently asked questions
Why 21 days therapy and 7 days break?
The break interval reduces frequency and severity of typical side effects such as hand-foot skin reaction and oral mucositis. It also allows recovery of the skin barrier and mucosa. Cyclic use is part of the approved standard therapy.
Can I manage hand-foot skin reaction proactively?
Yes. Before therapy: pedicure, removal of calluses, soft shoes and cushioning insoles. During therapy: regular use of urea-containing creams (10 to 25 %), and salicylic-acid-containing ointments if needed. With strong reactions, pause or reduce the dose early.
Why shouldn't I eat a fatty meal?
A high-fat meal (over 600 kcal and more than 30 % fat) can reduce regorafenib absorption by about 40 %. A light, low-fat meal ensures optimal and reproducible drug uptake.
What can I do about fatigue?
Fatigue is a very common side effect and not always dose-dependent. Helpful: regular moderate exercise, sufficient sleep, breaks during the day, balanced diet, and treatment of anaemia or hypothyroidism if present. With persistent exhaustion, dose reassessment can be useful.
Sources
- EMA Stivarga (regorafenib) EPAR
- BfArM Federal Institute for Drugs and Medical Devices
- AWMF oncology guidelines CRC, GIST, HCC
- Gelbe Liste regorafenib monograph
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