Sunitinib: Oral Multikinase Inhibitor (TKI) in Renal Cell Carcinoma, GIST and NET
Sunitinib (trade name Sutent, Pfizer) is a first generation oral multikinase inhibitor (TKI) and was approved in Europe in 2006. It inhibits several tyrosine kinases simultaneously, particularly VEGFR (Vascular Endothelial Growth Factor Receptor 1, 2, 3), PDGFR alpha and beta (Platelet Derived Growth Factor Receptor), KIT, FLT3 and RET. This multikinase inhibition explains both the antiangiogenic and the direct antitumour action.
Sunitinib has revolutionised the therapy of metastatic renal cell carcinoma and is also standard in gastrointestinal stromal tumour (GIST) and pancreatic neuroendocrine tumours (pNET). With the introduction of newer therapies (cabozantinib, lenvatinib, pazopanib, tivozanib in RCC, as well as immune checkpoint inhibitors), the role of sunitinib has changed in some indications, but it remains an important option, especially in first line and in specific patient groups.
Mechanism of Action
Sunitinib competitively binds to the ATP binding site of several tyrosine kinase receptors and blocks their phosphorylation activity. The inhibited receptors control signalling pathways for tumour growth (KIT, FLT3, RET), angiogenesis (VEGFR 1, 2, 3) and stromal activation (PDGFR alpha, beta).
VEGFR inhibition leads to reduction of tumour vessel neogenesis (antiangiogenic effect), which is highly effective especially in highly vascularised tumours such as renal cell carcinoma. KIT inhibition explains the action in GIST, which in over 80 percent of cases shows a constitutively activated KIT mutation.
Pharmacokinetically, sunitinib is orally absorbed independently of food (with or without meals). Half life approximately 40 to 60 hours, the active metabolite even has a half life of 80 to 110 hours, which explains the slow accumulation over several days. Metabolism via CYP3A4. Elimination predominantly biliary.
Indications
- Metastatic or locally advanced renal cell carcinoma (mRCC): first line and in subsequent lines, often combined or alternated with immune checkpoint inhibitors
- Gastrointestinal stromal tumour (GIST): after failure or intolerance of imatinib
- Pancreatic neuroendocrine tumours (pNET): in unresectable or metastatic tumours
- Adjuvant therapy after nephrectomy in high risk renal cell carcinoma: evaluated in some studies, role disputed
- Off label: thyroid carcinoma (medullary), HCC, sarcomas, other VEGF driven tumours
Dosage and Administration
Standard mRCC and GIST: 50 mg once daily orally for 4 weeks, followed by 2 weeks off (4/2 schedule). The break reduces toxicity and allows recovery of normal tissues.
pNET: 37.5 mg once daily continuously (without break).
In renal insufficiency: generally no dose adjustment. In hepatic insufficiency: dose adjustment in moderate to severe insufficiency.
With strong CYP3A4 inhibitors: dose reduction to 37.5 mg, with strong inducers dose increase to 87.5 mg possible, individually based on effect and toxicity.
Administration: with or without food, ideally at the same time of day. With nausea and vomiting, taking with meals can help.
Adverse Effects
Very common: fatigue (one of the main reasons for therapy adjustment), diarrhoea, nausea, stomatitis, hand foot syndrome (hyperkeratosis, pain, swelling on palms and soles), rash, taste alterations, hypertension, hypothyroidism, bone marrow suppression with neutropenia, thrombocytopenia and anaemia, hair lightening (pigment loss), yellowish skin colour.
Serious: heart failure and left ventricular dysfunction, hypertensive crises, thromboembolism including stroke and myocardial infarction, severe haemorrhages, gastrointestinal perforation, nephrotic syndrome, acute pancreatitis, severe hepatotoxicity, tumour lysis syndrome with large tumour masses, severe skin reactions (Stevens Johnson syndrome), rarely necrotising fasciitis.
Important: hypertension under sunitinib is a class adverse effect of antiangiogenic TKIs. Close blood pressure monitoring (initially daily, then weekly) and antihypertensive therapy if necessary are essential. Hypothyroidism often develops insidiously, regular TSH monitoring is standard.
Interactions
- Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, HIV protease inhibitors): increased sunitinib levels, dose reduction to 37.5 mg
- Strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St. John's wort): reduced sunitinib levels, dose increase to 87.5 mg possible
- QT prolonging substances: additive QT prolongation, caution and ECG monitoring
- Anticoagulants: increased bleeding risk in thrombocytopenia
- Other antiangiogenic substances: additive toxicity (hypertension, wound healing disorder, bleeding)
Special Considerations
Pregnancy and breastfeeding: contraindicated. Reliable contraception during and at least 4 weeks after therapy. Contraception is also recommended in men.
Before starting therapy: echocardiography to assess LVEF, ECG (QT), blood pressure, TSH, blood count, liver transaminases, creatinine, urinalysis (proteinuria).
Monitoring during therapy: blood count and blood pressure weekly in the first 2 months, then monthly; TSH every 3 months; LVEF check on symptoms or risk factors; urinalysis on suspicion of nephrotic syndrome.
Wound healing disorders: sunitinib inhibits wound healing via antiangiogenic action. Before elective surgical procedures, therapy should be paused 1 to 2 weeks beforehand and not restarted postoperatively before completion of wound healing.
Adherence: the correct intake according to schedule (4 weeks therapy, 2 weeks break) is important. With toxicity, the break can be extended or the dose reduced, which often improves tolerability without significantly reducing efficacy.
You may also be interested in
- Imatinib, first line in GIST
- Cabozantinib, another TKI in mRCC and HCC
- Pazopanib, another TKI in mRCC and sarcomas
- Lenvatinib, multikinase inhibitor in several tumours
- Nivolumab, PD 1 inhibitor in mRCC and other tumours
Frequently Asked Questions
What is a multikinase inhibitor?
Multikinase inhibitors are agents that inhibit several tyrosine kinase receptors simultaneously. Unlike highly selective inhibitors (e.g. imatinib for BCR ABL in CML), they block many signalling pathways in parallel, which can be advantageous in tumours with several activated pathways. The disadvantage is broader adverse effects, because normal tissue functions are also affected.
What is hand foot syndrome?
Hand foot syndrome (palmar plantar erythrodysaesthesia) is a skin disorder on the palms and soles with hyperkeratosis, pain, swelling, burning and sometimes blistering. It occurs in many multikinase inhibitors and some chemotherapies. Treatment with skin care measures (rich creams, avoidance of pressure, cooling measures), in severe cases therapy break or dose reduction.
Why do I get high blood pressure under sunitinib?
The inhibition of VEGFR reduces nitric oxide production in the vessels and leads to vasoconstriction and hypertension. This class adverse effect of antiangiogenic TKIs occurs in about 30 percent of patients, often already in the first weeks. Treatment with classic antihypertensives (ACE inhibitors, sartans, calcium antagonists) is usually well effective. Hypertension is often reversible after end of therapy.
Why the break after 4 weeks of therapy?
The 4 weeks of therapy plus 2 weeks of break schedule was established in the registration studies and reduces cumulative toxicity (bone marrow suppression, hand foot syndrome, mucositis). During the break, normal tissues recover, while the antitumour effect continues through the long half life. In pNET, treatment is continuous without break, because the toxicity at the lower dose (37.5 mg) is more tolerable.
Sources
- EMA, Sutent (Sunitinib) EPAR
- DGHO Onkopedia, Renal Cell Carcinoma and GIST
- Gelbe Liste, Sunitinib active substance profile
- BfArM, German Federal Institute for Drugs and Medical Devices
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