Fruquintinib: highly selective VEGFR tyrosine kinase inhibitor
Fruquintinib (brand name Fruzaqla) is a highly selective oral inhibitor of VEGF receptors 1, 2 and 3. It was first approved in China in 2018, followed by FDA approval in 2023 and EMA approval in 2024 for the treatment of previously treated metastatic colorectal cancer (mCRC). Fruquintinib differs from older multikinase inhibitors such as regorafenib by markedly higher selectivity for VEGFR, which can translate into a more favourable toxicity profile.
The pivotal FRESCO 2 trial in mCRC after failure of all standard lines showed a significant overall survival benefit versus placebo. Fruquintinib is therefore positioned among modern reserve therapies in the late line of metastatic colorectal cancer.
Mechanism of action
VEGF receptors 1, 2 and 3 are key enzymes of angiogenesis. Tumours need a continuous blood supply for growth and stimulate new vessel formation through VEGF ligands. Fruquintinib competitively binds the ATP binding site of the VEGFR tyrosine kinases and blocks downstream signalling.
Compared with multikinase inhibitors such as regorafenib or lenvatinib, fruquintinib is highly selective: other kinases are inhibited only at significantly higher concentrations. This translates into a modulated adverse event profile with less hand foot skin reaction, less mucositis and less diarrhoea than broad TKIs.
Oral bioavailability is high; the half life is around 42 hours. Fruquintinib is metabolised mainly via CYP3A4.
Indications
- Metastatic colorectal cancer (mCRC): after failure of all standard lines including fluoropyrimidines, oxaliplatin, irinotecan, anti VEGF and anti EGFR therapies and where appropriate regorafenib or trifluridine tipiracil
- Other solid tumours in clinical development: gastric cancer, NSCLC, endometrial cancer in trials
Fruquintinib is not licensed for first line therapy. A prerequisite is comprehensive prior therapy in line with current guidelines.
Dosing and administration
Standard dose: 5 mg orally once daily, 21 days on followed by 7 days off. One cycle lasts 28 days.
The drug is taken regardless of meals, ideally at the same time each day. Tablets are swallowed whole with water.
Dose modification: stepwise reduction to 4 mg, 3 mg per day or treatment pause for toxicity. Repeated severe adverse events lead to discontinuation.
Monitoring: blood pressure weekly during the first weeks, then every 2 to 4 weeks. Blood count, liver enzymes, thyroid, urinary protein every 2 to 4 weeks. Imaging every 6 to 12 weeks to assess response.
Adverse effects
Very common: hypertension, asthenia, hand foot skin reaction (less than with multikinase inhibitors), diarrhoea, proteinuria, mucositis, anorexia, hypothyroidism.
Common: hoarseness, abdominal pain, nausea, vomiting, pruritus, rash, anaemia, thrombocytopenia, neutropenia, raised liver transaminases.
Uncommon: hypertensive crisis, bleeding, gastrointestinal perforation, fistula formation, thromboembolic events, posterior reversible encephalopathy syndrome (PRES), wound healing problems.
Rare: acute liver failure, severe skin reactions.
Key points:
- Hypertension occurs in the majority of patients, often in the first weeks. Antihypertensive therapy should be in place at start or initiated promptly
- Check proteinuria regularly, particularly during the early treatment phase
- Hypothyroidism is common and easily replaced; measure TSH before and during therapy
- Pause therapy before and after surgical procedures because of wound healing concerns
Interactions
- Strong CYP3A4 inhibitors (itraconazole, ketoconazole, ritonavir, clarithromycin): raised levels, caution or dose reduction
- Strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St John's wort): reduced levels, avoid the combination if possible
- Other antiangiogenic agents (bevacizumab, aflibercept): additive toxicity, avoid combinations outside trials
- Anticoagulants: increased bleeding risk, INR monitoring
- Live vaccines: contraindicated
Special considerations
Pregnancy: contraindicated, teratogenic potential. Reliable contraception during therapy and for at least 2 weeks after the last dose for both sexes.
Breastfeeding: contraindicated.
Surgery: pause fruquintinib at least 2 weeks before elective surgery because of wound healing problems and bleeding risk. Restart only after wound healing is complete.
Hypertension: monitor blood pressure regularly and adapt antihypertensive therapy as needed. In hypertensive crisis interrupt therapy immediately.
Thyroid: measure TSH at baseline and every 2 to 3 months, replace with levothyroxine if necessary.
Patient communication: therapy is a reserve line after several previous regimens. Realistic expectations about effect and adverse events make treatment easier. Consistent management of adverse events, particularly early treatment of hypertension, preserves quality of life on therapy.
Related substances
- Regorafenib, established multikinase inhibitor in mCRC
- Sotorasib, KRAS G12C inhibitor in NSCLC
- Sorafenib, multikinase inhibitor in HCC and RCC
- Sunitinib, multikinase inhibitor in RCC
- Aflibercept, VEGF trap as systemic antiangiogenic therapy
Frequently asked questions
How does fruquintinib differ from regorafenib?
Fruquintinib inhibits VEGFR 1, 2 and 3 highly selectively. Regorafenib is a multikinase inhibitor that also blocks PDGFR, FGFR, KIT and RAF. The result is a slightly different adverse event profile: less hand foot skin reaction and mucositis, similar incidence of hypertension and proteinuria. Clinically both agents are options in late line mCRC.
What can I do about hypertension?
Hypertension is the most frequent adverse event. Important measures are regular home blood pressure monitoring, low salt diet, sufficient activity and where needed pharmacological therapy with ACE inhibitors, ARBs or calcium channel blockers. With stable control therapy can usually continue.
How is response assessed?
Imaging with CT or MRI every 6 to 12 weeks, clinical assessment of symptoms, tumour markers such as CEA in colorectal cancer and quality of life. The aim is stabilisation or reduction of tumour burden.
What to do in a hypertensive crisis?
Acute very high blood pressure with symptoms such as headache, visual disturbance or breathlessness needs immediate medical attention. Pause fruquintinib, intensify blood pressure control and search for triggers. After stabilisation therapy can often be resumed at a reduced dose.
Sources
- EMA European Medicines Agency
- BfArM German Federal Institute for Drugs and Medical Devices
- AWMF S3 guideline colorectal cancer
- Gelbe Liste fruquintinib monograph
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