Crizotinib

Patients with advanced-stage or metastatic non-small cell lung cancer have a grim prognosis when first-line chemotherapy fails. Some cytotoxic drugs such as docetaxel and pemetrexed prolong overall survival by a few months, but at a cost of severe toxicity. Crizotinib (Xalkori*, Pfizer), a drug that inhibits ALK (among other tyrosine kinases) has been authorised for use in patients whose tumours overexpress this tyrosine kinase. Preliminary results of a comparative, randomised but unblinded trial in 347 patients suggest that crizotinib delays cancer progression and death more effectively than pemetrexed or docetaxel (median 7.7 months versus 3 months). However, it remains to be seen whether or not this translates into longer overall survival. Two uncontrolled trials including 136 and 119 patients also suggest that crizotinib delays tumour progression and death by about 8 months. Crizotinib is highly toxic, causing gastrointestinal, visual and hepatic disorders, cardiac arrhythmias (including QT prolongation) and pneumonia. These adverse effects were all more frequent than with docetaxel or pemetrexed. Some of these effects are more difficult to predict and manage than haematological disorders, which are the main adverse effects of docetaxel and pemetrexed. Crizotinib is extensively metabolised by cytochrome P450 isoenzymes and also inhibits P-glycoprotein, creating a risk of numerous pharmacokinetic interactions. Other interactions, with drugs that prolong the QT interval, may increase the risk of serious adverse effects. In practice, in patients with non-small cell lung cancer overexpressing ALK tyrosine kinase in whom first-line chemotherapy has failed, crizotinib appears to delay cancer progression and death, but at a cost of serious adverse effects. Further evaluation of crizotinib in well-designed comparative trials is needed before deciding whether or not to include it in the therapeutic arsenal.