Anticancer agent - canertinib
Transmembrane receptor tyrosine kinases mediate the internal transmission of extracellular signals, and cancer can result if these signalling pathways are disrupted.
Transmembrane receptor tyrosine kinases mediate the internal transmission of extracellular signals, and cancer can result if these signalling pathways are disrupted.
Among these are the epidermal growth factor receptors (EGFR), also referred to as HER. Nearly two-thirds of human cancers are thought to involve some malfunction or alteration in an EGFR receptor, and these cancers are particularly likely to prove aggressive. Drugs that inhibit tyrosine kinases thus have great potential as anticancer agents.
Pfizer has been developing canertinib to treat cancer.1 The small molecule drug is an irreversible inhibitor of all four types of EGFR receptor and competes with ATP in the tyrosine kinase domain. Several clinical trials have been carried out, including a Phase I study in patients with advanced stage cancer.2 They were given the drug once a week in doses of 100, 200, 400, 500 and 560mg for three weeks, with cycles being repeated every 28 days. Reversible dose limiting hypersensitivity was seen in two patients given the highest dose, but prophylaxis with diphen-hydramine allowed dosing to continue. One of the patients achieved stable disease over eight cycles.
A second Phase I study was carried out in 24 patients with advanced stage cancer.3 They were given four-week courses of 250mg and 200mg oral daily doses of canertinib for seven days every other week. Disease limiting toxicities were seen at the higher dose. Fourteen of the patients were evaluable for tumour response. Four of these achieved stable disease, with median time to progression of six and a half months.
In a dose escalating study, 32 patients with advanced cancer were given 300 to 560mg/day of the drug orally over 14 days in a 21 day cycle.4 The maximum tolerated dose was 450mg. No patients achieved a complete or partial response, but six had stable disease. No significant increase in toxicity was seen compared with the shorter dosing regimens.
An open label Phase II trial has been carried out in 105 patients with platinum refractory or recurrent ovarian cancer, who had had a median of four prior chemotherapy regimens.5 Subjects were given oral doses of either 50mg or 200mg of the drug each day for 21 days in a 28 day cycle. No responses were observed, but a total of 34% of the patients given 200mg and 26% of those given 50mg achieved stable disease. One year survival rates were 38%. The most common drug-related adverse events were gastrointestinal toxicity, asthaenia and rash.