Sorafenib: multikinase inhibitor TKI in HCC, RCC, thyroid cancer
Sorafenib (brand name Nexavar) was approved in the USA in 2005 and in the EU in 2006 as the first orally available multikinase inhibitor for solid tumours. With its approval in hepatocellular carcinoma (HCC) it revolutionised systemic therapy of this previously hard-to-treat disease. Later, sorafenib was also approved in metastatic renal cell carcinoma (RCC) and in differentiated thyroid cancer with resistance to radioiodine therapy.
The pivotal SHARP trial showed a significant prolongation of overall survival versus placebo in HCC, sustainably changing treatment standards. Today, several follow-on substances exist (lenvatinib, cabozantinib, regorafenib), but sorafenib remains an established pillar.
Mechanism of action
Sorafenib is an orally available tyrosine kinase inhibitor with a broad profile. It inhibits several kinases with varying selectivity:
- Angiogenic kinases: VEGFR1, 2, 3 and PDGFR beta
- Oncogenic kinases: BRAF, CRAF, KIT, FLT3
- Indirectly the RAS pathway and downstream signalling cascades
This results in inhibition of tumour vessel formation and a direct antiproliferative effect on tumour cells. Sorafenib mainly acts cytostatically; complete tumour regression is rare; clinically, disease stabilisation and slowing of progression dominate.
Sorafenib is metabolised hepatically via CYP3A4 and glucuronidation. Half-life is 25 to 48 hours; twice-daily dosing keeps stable plasma levels.
Indications
- Advanced hepatocellular carcinoma (HCC): after failure of local therapies or in non-resectable disease
- Metastatic renal cell carcinoma (RCC): after failure of cytokine therapy or as first line
- Differentiated thyroid cancer (papillary, follicular, Hürthle cell): in radioiodine-refractory advanced disease
- Off-label: acute myeloid leukaemia with FLT3 mutation, desmoid tumours, some soft tissue sarcomas
Dosing and administration
Standard dose: 400 mg twice daily, total 800 mg per day, taken without a meal or with a low-fat meal. A high-fat meal reduces bioavailability by about 30 %.
Dose reduction: with toxicity to 400 mg once daily, then 400 mg every other day. With repeated severe side effects consider stopping therapy.
Treatment continues until disease progression or unacceptable toxicity. Close clinical observation and regular imaging (every 2 to 3 months) are essential.
Side effects
Very common: diarrhoea, hand-foot skin reaction, rash, pruritus, alopecia, fatigue, hypertension, anorexia, nausea, vomiting, abdominal pain, increased lipase and amylase.
Common: hoarseness (dysphonia), stomatitis, wound healing disorders, raised liver transaminases, weight loss, hypothyroidism, anaemia, thrombocytopenia, leukopenia, hypocalcaemia, hypophosphataemia.
Uncommon: hepatitis, hypertensive crisis, cardiac ischaemia, gastrointestinal perforation, pancreatitis, reversible posterior leukoencephalopathy syndrome (RPLS), nephrotic syndrome.
Rare: acute liver failure, Stevens Johnson syndrome, severe skin reactions, thromboembolic events.
Hand-foot skin reaction (HFSR):
- Most common dose-limiting side effect, especially in the first 2 to 6 weeks
- Symptoms: painful redness, swelling, hyperkeratosis, blistering on hands and feet
- Prevention: pedicure before therapy, soft shoes, avoid pressure points, urea-containing skin care
- Treatment: dose reduction or break, local cooling, urea-containing and keratolytic care products
Interactions
- Strong CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, St John's wort): level fall, loss of effect
- UGT1A1 or UGT1A9 substrates (irinotecan): raised levels of co-medication, toxicity
- Doxorubicin, paclitaxel: pharmacokinetic changes, individual clinical relevance
- Anticoagulants (warfarin): increased bleeding risk, INR monitoring
- Live vaccines: contraindicated
Special considerations
Pregnancy: contraindicated, teratogenic potential. Reliable contraception during and several months after therapy for both sexes.
Breastfeeding: contraindicated.
Surgery: pause sorafenib 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. Marked hypertension may indirectly mark efficacy but also poses risks.
Thyroid: hypothyroidism is common. Check TSH before therapy and every 2 to 3 months; substitute with levothyroxine as needed.
Patient communication: realistic expectations matter. Sorafenib does not aim at tumour regression but at disease stabilisation. This expectation prevents disappointment and supports adherence, especially during phases with side effects.
Related substances
- Regorafenib, another multikinase inhibitor
- Sunitinib, multikinase inhibitor focused on RCC and GIST
- Dasatinib, BCR-ABL and SRC inhibitor
- Sotorasib, KRAS G12C inhibitor
- Fruquintinib, highly selective VEGFR TKI
Frequently asked questions
How does sorafenib act on the tumour?
Sorafenib inhibits several tyrosine kinases, especially those responsible for vessel formation (angiogenesis) and tumour cell growth. The tumour is therefore less well supplied with blood and growth slows. The aim is usually not complete regression but stabilisation and slowing of disease.
How can I prevent hand-foot skin reaction?
A pedicure and removal of calluses before starting therapy is recommended. During therapy: soft, well-fitting shoes, avoid pressure points, regular use of urea-containing creams (10 to 25 %). With early symptoms, adjust the dose early to avoid more severe courses.
Why not eat too fatty?
A high-fat meal reduces sorafenib bioavailability by about 30 %. Take on an empty stomach or with a low-fat meal to ensure consistent drug levels.
How is therapy success measured?
Imaging with CT or MRI every 2 to 3 months, clinical assessment of symptoms, tumour markers (e.g. AFP in HCC) and quality of life. With progression, therapy is reassessed. Some patients also benefit from follow-up therapies such as regorafenib or cabozantinib.
Sources
- EMA Nexavar (sorafenib) EPAR
- BfArM Federal Institute for Drugs and Medical Devices
- AWMF oncology guidelines HCC, RCC, thyroid
- Gelbe Liste sorafenib monograph
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