Axitinib for renal cell carcinoma
- First published 28 September 2012
- Aust Prescr 2012;35:208-10
- 3 December 2012
- DOI: 10.18773/austprescr.2012.092
Approved indication: renal cell carcinoma
1 mg and 5 mg tablets
Australian Medicines Handbook section 14.2.3
Axitinib is another addition to the group of tyrosine kinase inhibitors – sorafenib, sunitinib and pazopanib – for renal cell carcinoma. Its anti-angiogenic effects stem from its inhibition of the vascular endothelial growth factor receptors 1, 2 and 3.
Early trials of axitinib in patients with refractory metastatic disease were promising.1,2 In a more recent open-label randomised phase III trial of 723 patients, axitinib (5 mg twice daily) was compared with sorafenib (400 mg twice daily). At enrolment, patients had progressive disease despite previous treatment with sunitinib, bevacizumab plus interferon alfa, temsirolimus or cytokines. Dose increases were allowed with axitinib (maximum 10 mg twice daily) but not with sorafenib. The patients who received axitinib survived for significantly longer without disease progression than those who received sorafenib (median of 6.7 months vs 4.7 months).3 However, overall median survival was similar between treatments (20.1 months vs 19.2 months).
The safety of axitinib seems to be comparable to sorafenib. Adverse reactions were very common, with over half of the patients in the trial having their axitinib dose reduced or interrupted because of an event. Diarrhoea (55% of patients), hypertension (40%), fatigue (39%), decreased appetite (34%), nausea (32%), dysphonia (31%) and hand-foot syndrome (27%) were the most common. In the phase III trial, 16% of patients had a bleeding event and just over a third had anaemia. Conversely, 10% of patients had increased haemoglobin so monitoring this parameter is important. Thrombocytopenia (15%), lymphopenia (33%), creatinine elevation (55%), hypocalcaemia (39%) and lipase elevation (27%) were also common. Axitinib can affect thyroid (19.2% of patients had hypothyroidism) and liver function so these should be measured at baseline and regularly during treatment.
High blood pressure is a problem with axitinib and should be controlled with antihypertensives. In persistent cases, the axitinib dose may need to be reduced, or interrupted then restarted at a lower dose when blood pressure has normalised. Proteinuria occurs with axitinib (10.9% of patients) and should be monitored before and during treatment.
In the axitinib arm of the phase III trial, one patient died of a cerebrovascular accident and another of pulmonary embolism. Axitinib should be used with care in patients with a history of such events, particularly as they were excluded from the trial. There was also a death from gastric haemorrhage and axitinib should not be used in patients who have recently had gastric bleeding. Gastrointestinal perforation and fistulas have been reported with axitinib and patients should be monitored for symptoms during treatment.
One patient in the trial developed reversible posterior leukoencephalopathy syndrome. It can present with headache, seizure, lethargy, confusion, blindness and other neurological symptoms, with or without hypertension. Treatment should be stopped if this is suspected.
Following an oral dose of axitinib, peak plasma concentrations are reached within four hours and steady state is achieved after 2–3 days. Axitinib is metabolised in the liver and the dose should be reduced in patients with moderate hepatic impairment. Axitinib is excreted in the faeces and urine and caution is urged in patients with end-stage renal disease.
Axitinib is metabolised mainly by cytochrome P450 (CYP) 3A4, but also by CYP1A2, CYP2C19 and UGT1A1 so there is a potential for drug interactions. Concomitant use of strong CYP3A4 inhibitors (such as ketoconazole, clarithromycin, grapefruit juice) or inducers (such as rifampicin, carbamazepine, St John's wort) may affect axitinib concentrations. If these drugs cannot be avoided, adjustment of the axitinib dose is recommended.
The prognosis for patients with advanced renal cell carcinoma is poor. Axitinib provides another option for those who have relapsed despite previous treatment. Although it may temporarily reduce disease progression, it does not seem to prolong overall survival any more than sorafenib. It is not known how axitinib will compare to other treatments for this disease.
The Transparency Score is explained in New drugs: transparency, Vol 37 No 1, Aust Prescr 2014;37:27.
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