Kinases are enzymes that act by transferring phosphate ligands from energy sources such as ATP to small molecule substrates such as proteins, sugars and nucleotides. There are a huge number of substrate specific kinases that play important roles in signalling, and many are being investigated as potential targets for anticancer agents.
Regorafenib is a broad spectrum diphenyl-urea kinase inhibitor that is structurally related to the existing kidney and liver cancer drug sorafenib, and is being developed by Bayer for the treatment of cancers such as colorectal, non-small cell lung, liver and kidney cancers, and gastrointestinal stromal tumours.1
The orally available drug acts against many different kinases, including both vascular endothelial growth factors 1 and 2, MAP kinase p38, c-RAF kinase and a number of others. The result is an interference with the angiogenesis process. It also affects the oncogenesis process.
In one Phase I trial in patients with advanced refractory non-small cell lung cancer, 23 subjects were given oral doses of 100 or 120mg of the drug once a day in repeating continuous 21 day cycles.2 All the patients had been extensively pretreated with drugs such as carboplatin, pemetrexed, EGFR inhibitors, docetaxel, paclitaxel, bevacizumab and cisplatin. The most common adverse events included hand-foot skin reaction, pain in the extremities, hypo-thyroidism and rash.
Of the 17 evaluable patients, 13 had stable disease for at least six weeks after the start of the trial, and the disease remained stable for at least 12 weeks in four of them. One had a progression-free survival for 279 days, with a tumour reduction in excess of 30%. The disease had progressed at the first evaluation in the remaining four evaluable patients.
A further Phase I trial was carried out in patients with advanced solid tumours. In this dose escalation study, a total of 38 patients with progressive disease were given oral doses once a day in continuous 21 day cycles until discontinuation as a result of toxicity or disease progression occurred.3 Subjects with tumours such as colorectal, thyroid, adenoid cystic carcinoma and head and neck carcinoma were given doses of 20–140mg of the drug.
The most common drug-related adverse events included rash, hand-foot skin reaction, mucositis, extremity pain, fatigue and diarrhoea. Two of 11 patients had a dose limiting toxicity in the first two cycles at the 100mg dose. Two of the 36 evaluable patients achieved a partial response, and 22 had stable disease for at least six weeks, one of whom, with hepatocellular carcinoma, had stable disease for 90 weeks. Phase II and III trials are under way.
1. S.M. Wilhelm et al. Int. J. Cancer 2011, 129, 245
2. M.S. Kies et al. J. Clin. Oncol. 2010 (15, suppl), Abst 7585
3. T. Shimizu et al. J. Clin. Oncol. 2010 (15, suppl), Abst 3035