PHILADELPHIA - The drug gefitinib (Iressa) was approved by the U.S. Food and Drug Administration (FDA) in May 2003 under the agency's accelerated approval program for the treatment of patients with non-small cell lung cancer (NSCLC) who had failed two or more courses of chemotherapy. Consistent with the requirements of accelerated approval, the sponsoring company continued to study the drug to verify the expected clinical benefit. In December 2004, the FDA released a statement notifying the failure of a large clinical trial of gefitinib to show an overall survival advantage compared to placebo in treating patients with lung cancer. In June 2005, FDA issued a new label for gefitinib "that limits use to patients with cancer who in the opinion of their treating physician, are currently benefiting, or have previously benefited, from Iressa treatment."
However, oncologists believe that Iressa still holds promise and continue investigating its potential. Several studies presented at the Annual International Conference on Molecular Targets and Cancer Therapeutics coordinated by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI) and the European Organisation for Research and Treatment of Cancer (EORTC) explore the ways in which gefitinib may work on tumors and which patients may benefit the most.
- Molecular markers may be the key to ensuring successful treatment with gefitinib.
- Lung cancer patients with these markers may have a greater chance of survival benefit with gefitinib treatment.
- Lung cancer patients' chance of survival with gefitinib may lie with an inherited genetic contribution in patients with a good disease performance status.
Epidermal Growth Factor (EGFR), K-Ras and B-Raf Mutation Status and Clinical Outcome to Gefitinib (Iressa) in Phase III Placebo-Controlled Study (ISEL) in Advanced Non-Small-Cell Lung Cancer (NSCLC) (Abstract 3103)
In large Phase II studies (Iressa Dose Evaluation in Advanced Lung Cancer 1 and 2, IDEAL) gefitinib has produced objective tumor responses in 12 to 18 percent of patients with refractory advanced NSCLC (aNSCLC) and symptomatic improvement in more than 40 percent of all patients in the study. ISEL (The Iressa Survival Evaluation in Lung Cancer trial) a Phase III survival study, evaluating 1,692 patients taking 250 mg/day of gefitinib or placebo, showed some improvement in survival compared to placebo, but did not reach statistical significance in the overall or adenocarcinoma populations. However, significant improvement in survival was seen in the subgroups of patients of Asian origin and in never smokers.
Researchers from AstraZeneca Pharmaceuticals used the ISEL study to determine why certain subgroups of patients derive greater clinical benefit with gefitinib. Specifically, investigators studied the effects of mutations in the EGFR, K-Ras and B-Raf genes. EGFR, or epidermal growth factor receptor, is implicated in the development and progression of a number of solid tumors and is the target for gefitinib. K-Ras and B-Raf are signaling molecules in the EGFR pathway and mutations in these genes may lead to resistance to gefitinib. Of the 215 evaluable tumor samples, 26 patients were EGFR mutation positive, and of 152 patients studied, 12 samples showed evidence of K-Ras mutation. No analyzed tumor samples showed evidence of both EGFR and K-Ras mutations. Additionally, no B-Raf mutations were found in the 118 patients with available samples.
"The ISEL study provided us the opportunity to investigate whether molecular markers will predict clinical outcome of gefitinib in patients with NSCLC," according to Brian Holloway, Science Director for Iressa at AstraZeneca Pharmaceuticals and lead author of the study. "When oncologists are able to distinguish between predictive and prognostic factors, they are better equipped to provide the care necessary for their patients' survival."
Molecular Analysis of EGFR Gene Copy Number, EGFR Expression and Akt Activation Status in Advanced Non-Small Cell Lung Cancer (NSCLC) Treated with Gefitinib or Placebo (ISEL Trial) (Abstract 3274)
The Iressa Survival Evaluation in Lung Cancer (ISEL) trial is a large randomized trial conducted in 1,692 patients with refractory NSCLC who received either gefitinib 250 mg/day or placebo. Some survival improvement was reported with gefitinib, although statistical significance was not reached.
Therefore, researchers from the University of Colorado Cancer Center decided to further study the patients in this trial to determine the relationship between clinical outcome of the trial with EGFR gene copy number, EGFR protein expression and Akt activation status. Results showed that when genetic markers of NSCLC were studied, subgroups of patients treated with gefitinib were identified with specific biomarkers that appear to predict for an increase in survival. P-AKT, protein kinase B, is a major culprit in many kinds of cancer due to its ability to cause cell growth and overcome natural apoptosis (programmed cell death) signals that cells receive.
The EGFR study population had similar demographics to the overall ISEL population, with the exception of fewer patients of Asian descent and fewer people who had never smoked. Tumors with high EGFR gene copy numbers were classified as FISH (fluorescent in situ hybridization)-positive. If nuclear staining was present, the tumor was classified as p-Akt positive. EGFR expression (the presence of EGFR) was tallied based on the intensity multiplied by the fraction of positive cells.
Thirty-one percent of patients tested FISH-positive, 41 percent tested p-Akt positive, and 68 percent tested positive for EGFR protein expression. The effect of gefitinib on survival was greater in FISH-positive than FISH-negative patients. Among FISH-positive patients, survival time appeared longer with gefitinib than placebo (8.3 versus 4.5 months), but gefitinib offered little survival benefit for FISH-negative patients. EGFR expression and p-Akt status were not significant survival predictors. Objective responses were observed in 16.4 percent of FISH-positive and 3.0 percent of FISH-negative patients, 10.1 percent of p-Akt-positive and 6.3 percent of p-Akt-negative patients, and 8.2 percent of EGFR protein-positive and 1.5 percent of EGFR-negative patients.
Inherited EGFR Variants and Survival in Patients with Non-Small Cell Lung Cancer (NSCLC) Treated with Gefitinib (Abstract #279)
Many Italian lung cancer patients with advanced NSCLC (aNSCLC) receive gefitinib orally (250 mg/day) as part of the Iressa Expanded Access Programme. Researchers from the Scientific Institute University Hospital San Raffaele, Milan, Italy, and the Johns Hopkins University School of Medicine studied 175 patients participating in the program to evaluate the association between germline (inherited material that comes from the eggs or sperm and is passed on to offspring) EGFR variants and overall survival with gefitinib.
Investigators identified an association of common germline EGFR promoter single-nucleotide polymorphisms (SNPs, common, but minute, variations that occur in human DNA at a frequency of one every 1,000 bases) with time to progression and overall survival that may suggest an inherited genetic contribution to the response to gefitinib treatment in patients with a good performance status (PS).
One hundred and seventy of the 175 patients were evaluated for genotyping studies (all or part of the genetic constitution of an individual or group) and survival. Median overall survival was 194 days; 55 patients had stable disease, 15 experienced partial response, and two had complete responses. "Investigators identified four distinct haplotypes (different combinations of genes or DNA polymorphisms), of which G-C (EGFR*1; frequency 45.5 percent) and T-C (EGFR*3; 43.6 percent, were the most common." Results showed that the percentage of patients with PS 2 was higher in patients without the EGFR*1 haplotype on one or more alleles (actual nucleotide sequence of a gene on a chromosome) (35 percent versus 15 percent).
A subset analysis was conducted in 139 patients with good performance status (PS 0 or 1). After adjusting for the effects of known prognostic factors that were associated in this set with overall survival, namely PS (0 versus 1), prior platinum-containing chemotherapy, and occurrence of rash or diarrhea, grade greater than one, during the first treatment cycle, the EGFR*1 haplotype was associated with worse survival. Additionally, an association was seen between the EGFR haplotype*1 and shorter progression free survival, although the significance of this result is borderline.
Founded in 1907, the American Association for Cancer Research is a professional society of more than 24,000 laboratory, translational, and clinical scientists engaged in cancer research in the United States and in more than 60 other countries. AACR's mission is to accelerate the prevention and cure of cancer through research, education, communication, and advocacy. This work is carried out through five major peer-reviewed scientific journals and high-quality scientific programs focusing on the latest developments in all areas of cancer research.
The National Cancer Institute, founded in 1971, is the principal United States government agency charged with coordinating the National Cancer Program. It facilitates international cooperation in clinical trials involving U.S. and foreign collaborating institutions.
The European Organisation for Research and Treatment of Cancer was organized in 1962 to conduct, develop, coordinate and stimulate laboratory and clinical research in Europe, and to improve the management of cancer and related problems by increasing the survival and quality of life for patients.