Cabozantinib for renal cell carcinoma
- First published 15 May 2018
- Aust Prescr 2018;41:92–3
- 1 June 2018
- DOI: 10.18773/austprescr.2018.024
Approved indication: renal cell carcinoma
20, 40 and 60 mg film-coated tablets
Australian Medicines Handbook section 14.2.4
Cabozantinib is a small molecule inhibitor of a number of tyrosine kinases that are thought to be involved in tumour growth and angiogenesis. It is indicated for patients with renal cell carcinoma that has progressed after being treated with a vascular endothelial growth factor receptor inhibitor such as sorafenib,1 pazopanib2 or axitinib.3
The approval of cabozantinib is based on an open-label phase III trial of 658 pre-treated patients with advanced disease. They were randomised to receive cabozantinib 60 mg or everolimus 10 mg once daily. Median progression-free survival (7.4 vs 3.9 months) and overall survival (21.4 vs 16.5 months) were longer with cabozantinib than with everolimus. The objective response rate (proportion of patients with a partial response) was also higher for cabozantinib (17% vs 3%) (see Table).4,5
Table: Efficacy of cabozantinib in advanced renal cell carcinoma
|Median progression-free survival||7.4 months||3.9 months|
|Objective response rate (proportion of patients with a partial response)||17%||3%|
|Median overall survival||21.4 months||16.5 months|
Based on reference 5.
The median duration of treatment with cabozantinib was 8.3 months. Dose reductions and interruptions were needed in 62% and 12% of patients.5 Adverse events were very common – the most frequently reported were diarrhoea (74%), fatigue (56%), nausea (50%), anorexia (46%), palmar-plantar erythrodysaesthesia (42%), hypertension (39%), vomiting (32%), weight loss (31%) and constipation (25%). Over two-thirds of patients had a serious adverse event.5 These included gastrointestinal perforation and fistulas, QT prolongation, haemorrhage and pulmonary embolism. Wound complications can also occur and cabozantinib should be stopped at least four weeks before scheduled surgery.
The recommended dose of cabozantinib is 60 mg once a day. This should be reduced to 40 mg once daily in patients with mild–moderate hepatic impairment. The drug should be used with caution in people with mild–moderate renal impairment and is not recommended for those with severe hepatic or renal impairment.
Patients should be advised not to eat for at least two hours before and one hour after taking cabozantinib. Following an oral dose, peak plasma concentrations are reached within 2–3 hours. The plasma half-life of cabozantinib is 99 hours and the drug and its metabolites are excreted in the faeces (54%) and urine (27%).
Cabozantinib is highly protein bound and there is a theoretical risk that it will displace concomitant warfarin so INR monitoring is recommended.
Cabozantinib is a substrate of cytochrome P450 (CYP) 3A4 so co-administration of strong inhibitors (e.g. ketoconazole) or inducers (e.g. rifampicin) increase and decrease cabozantinib concentrations respectively. Caution is therefore urged and long-term use of inhibitors and inducers should be avoided. Cabozantinib also inhibits P-glycoprotein in vitro and may increase concentrations of co-administered substrates such as dabigatran, digoxin, maraviroc, saxagliptin and tolvaptan.
Cabozantinib offers another option for patients who have relapsed renal cell carcinoma. In the trial, it prolonged overall survival for up to five months longer than everolimus. However, serious adverse effects are very common with cabozantinib and are likely to limit treatment. The drug is also approved overseas for medullary thyroid cancer.
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