Tyrosine-Kinase-Inhibitors May Be Effective in Common But Deadly Type of
A type of drug that blocks the binding of cancer-promoting proteins may be suitable for treatment-resistant non-small cell lung cancer (NSCLC), especially if a specific growth factor is activated, according to a case study published today in the Clinical Therapeutics section of The New England Journal of Medicine.
The article, written by a team of researchers while they were fellows at The University of Texas MD Anderson Cancer Center, outlines the available data about use of these drugs, known as oral tyrosine kinase inhibitors, in the treatment of lung cancer patients.
It is based on the case of a 64-year-old woman with Stage I adenocarcinoma (cancer) of the lung who had a right upper lobectomy, or surgical removal of part of her lung. She had never smoked. A year after treatment, the cancer had spread to the bone and liver. Although she then was treated with carboplatin, paclitaxel and bevacizumab, more bone metastases were found six weeks later.
"NSCLC is a deadly disease that is incurable once it has metastasized," said Don Gibbons, M.D., Ph.D., assistant professor in the Departments of Thoracic/Head and Neck Medical Oncology, and Molecular and Cellular Oncology at MD Anderson. "New approaches like erlotinib and gefitinib have proven benefit in a subset of patients, even with widely metastatic disease, and frequently these are less toxic than cytotoxic chemotherapy."
Erlotinib and gefitinib, known commercially as Tarceva and Iressa, are tyrosine kinase inhibitors, which block the binding of epidermal growth factor (EGF) with the epidermal growth factor receptor (EGFR) to stop cancer growth.
Co-authors were first author Vince D. Cataldo, M.D., Louisiana State University Health Sciences Center; Roman Perez-Soler, M.D., Albert Einstein College of Medicine; and Alfonso Quintas-Cardama, M.D., assistant professor, Department of Leukemia, MD Anderson Cancer Center.
Agents block growth factor binding
According to the American Cancer Society, lung cancer is the leading cause of cancer-related death in the United States, and each year it accounts for more than 157,000 deaths. About 90% of lung cancers are NSCLC. Even with new drugs, such as bevacizumab, the median five-year survival rate is 3.5%.
The dismal outlook for NSCLC has prompted researchers to look for new treatment approaches, including some - like erlotinib and gefitinib - that act on the epidermal growth factor receptor, which is activated in more than half of patients with NSCLC. This is the same protein targeted by the monoclonal antibody cetuximab, that was developed under the pioneering leadership of MD Anderson Cancer Center President John Mendelsohn, M.D.
Binding of epidermal growth factor (EGF) and other EGF-like growth factors to their receptors triggers cancer-promoting processes such as cell proliferation, protection from cell death, activation of new blood vessel formation and development of metastasis.
Research shows success in certain patients
In clinical trials, these agents have shown some success in NSCLC. Research suggests they may be as effective as standard chemotherapy for second- or third-line treatment in patients with advanced NSCLC. As first-line therapy, tyrosine kinase inhibitors appear to be less effective than standard chemotherapy in general but more effective for some patients, especially those with activating EGFR mutations. Some initial clinical trials have shown that women, patients of East Asian descent, patients who have never smoked and patients with adenocarcinomas who received erlotinib or gefitinib had higher rates of response and overall survival.
Because EGFR tyrosine kinase inhibitors are expensive and have shown relatively low response rates overall, a method is needed to identify the specific patient group that will benefit from them. EGFR mutational status is the most reliable predictor of response and benefit now. However, assessment of all patients with advanced NSCLC and subsequent treatment with an EGFR tyrosine kinase inhibitor for those with EGFR mutations has not shown to have an overall positive effect on survival. However, if a patient is known to have an EGFR mutation, therapy with an EGFR tyrosine kinase inhibitor is advisable.
Erlotinib is recommended in this case
Gibbons says their review of data suggests EGFR tyrosine kinase inhibitors should be considered in this case. Since erlotinib has been shown to be beneficial as second-line therapy in unselected patients, treatment without assessment of the EGFR mutational status is acceptable. Restaging studies should be conducted before therapy begins and six to eight weeks after to evaluate response. Therapy should continue until the cancer progresses.