Solid Tumors Small-molecule epidermal growth factor (EGF) antagonists act at the ATP binding site of the EGF receptor tyrosine kinase. In early clinical trials, gefitinib showed evidence of responses in a small fraction of patients with non-small cell lung cancer. Side effects were generally acceptable, consisting mostly of rash and diarrhea. Gefitinib was found to have antitumor activity mainly in the subset of patients with tumors containing activating mutations in the EGF receptor. Often patients who developed resistance to gefitinib have acquired additional mutations in the enzyme, similar to what was seen in imatinib-resistant CML. Erlotinib is another EGF receptor. | Chapter 081. Principles of Cancer Treatment Part 19 Solid Tumors Small-molecule epidermal growth factor EGF antagonists act at the ATP binding site of the EGF receptor tyrosine kinase. In early clinical trials gefitinib showed evidence of responses in a small fraction of patients with non-small cell lung cancer. Side effects were generally acceptable consisting mostly of rash and diarrhea. Gefitinib was found to have antitumor activity mainly in the subset of patients with tumors containing activating mutations in the EGF receptor. Often patients who developed resistance to gefitinib have acquired additional mutations in the enzyme similar to what was seen in imatinib-resistant CML. Erlotinib is another EGF receptor tyrosine kinase antagonist with somewhat superior activity to gefitinib in clinical trials in non-small cell lung cancer. Even patients with wildtype EGF receptors may benefit from erlotinib treatment. Lapitinib is a combined EGF receptor and erbB2 tyrosine kinase antagonist with activity in breast cancers refractory to anti-erbB2 antibodies. In addition to the p210bcr-abl kinase imatinib also has activity against the c-kit tyrosine kinase activated in gastrointestinal stromal sarcoma and the platelet derived growth factor receptor PDGF-R activated by translocation in certain sarcomas. Imatinib has found clinical utility in these neoplasms previously refractory to chemotherapeutic approaches. Multitargeted kinase antagonists are small-molecule ATP site-directed antagonists that inhibit more than one protein kinase. Drugs of this type with prominent activity against the vascular endothelial growth factor receptor VEGFR tyrosine kinase have activity in renal cell carcinoma. Sorafenib is a VEGF-R antagonist with activity against the raf serine-threonine protein kinase as well. Sunitinib has anti-VEGF-R as well as anti-PDGF-R and anti-c-kit activity. It causes prominent responses as well as stabilization of disease in renal cell cancers and gastrointestinal
