Julia Draznin Maltzman, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: December 21, 2003
Lung cancer is the leading cause of cancer death of both men and women in the US. More people die of lung cancer in the US than from breast, colon, and prostate combined. Most who are diagnosed with lung cancer will die from their disease. Those who survive are plagued with symptoms that may interfere with their quality of life. Some of these symptoms include shortness of breath that limits activities of daily living, cough, coughing up blood, weight loss, blood loss leading to anemia, fatigue, and debilitation. Unfortunately, the presenting signs of this disease often occur at a late stage when cure is no longer an option. Front line chemotherapy has shown to improve survival by a few months; however, there are limited options are available for recurrent or refractory disease.
Cancer occurs when normal lung tissues loose the ability to control their cellular growth and differentiation. There are two major types of lung cancer ? Non Small Cell Lung Cancer (NSCLC) and Small Cell Lung Cancer (SCLC). The difference is primarily based on histology (what they look like under the microscope). These two types of lung cancers differ from one another by the velocity and mechanism of growth and spread. It is very important to distinguish between the two types, as prognosis and treatments vary. NSCLC is by far more common and, in general, grows more slowly than SCLC. NSCLC is further subdivided by different cell types, but the treatment is dictated by stage of disease and not cellular subtype.
Very early stage NSCLC is curable with surgery and chemotherapy. Conventional therapies for advanced NSCLC include chemotherapy and radiation. Despite low cure rates, these have been shown to improve the quality of life, reduce cancer-associated symptoms, and prolong overall survival. However, even with these currently available modalities, most cases of metastatic NSCLC are terminal and treatment goals are palliative. Most conventional chemotherapies achieve an objective response rate of about 20%-40%. Unfortunately, responses are not often durable, and median survival is in the order of months. In addition, these currently available treatments are toxic. Research and exploration for new and novel therapies has been driven largely by the inadequacy of our current regimens and a desire for more successful and less toxic options.
Consequently, a new class of medications has emerged called ?targeted therapies?. At their core, these drugs attempt to exploit the differences between normal and cancer cells. The concept of targeted therapies is that they focus on specific pathways that are aberrant in cancer and therefore do not affect the normal healthy tissues. In general, the side effect profile of targeted agents is thought to be less toxic than conventional cytotoxic therapies. Another advantage of targeted therapy is that, in general, there are fewer drug-drug interactions with these agents as opposed to chemotherapeutics. One such targeted therapy that has shown much promise in lung cancer is the inhibitor of a specific enzyme called a tyrosine kinase.
The Epidermal growth factor receptor (EGFR) is a receptor found on the cell surface of many different cancers. It is activated when a blood soluble protein binds to it. Only one specific protein (or few very specific proteins), can bind to any given receptor. The EGFR receptor is a glycoprotein (a protein with a sugar groups attached) that has tyrosine kinase (TK) activity. TK's have the ability to add a phosphate group on to a tyrosine amino acid within a given protein or even onto itself. The addition of a phosphate group is called phosphorylation. Protein phosphorylation that always accompanies activation of, EGFR, leads to the activation of multiple cellular pathways involved in tumor growth, differentiation, transformation, proliferation, metastasis, and inhibition of apoptosis. The TK proteins comprise the largest family of dominant oncogenes that are altered in lung cancer. EGFR is overexpressed in a variety of solid tumors including NSCLC. Some studies suggest that EGFR overexpression leads to worse outcome, however this has not been definitively proven.
Several drugs that block the activation of EGFR or its downstream signals have been under investigation as potential treatments in lung cancer. One of the more successful ones is gefitinib, (Iressa also called ZD 1839, Astra Zeneca). In fact, this drug has been so successful that the Food and Drug Administration (FDA) recently approved it for patients who failed conventional first line therapy.
Gefitinib, is a new type of cancer treatment that belongs to a group called small molecule inhibitors. It is a man-made chemical compound that specifically targets the EGFR TK portion. A phase I study of gefitinib as single therapy in patients with advanced solid tumor cancers, found that the NSCLC had the highest efficacy rate among all the other cancers.
Phase II data from two studies of gefitinib as single therapy in advanced NSCLC were reported. These are called the Iressa Dose Evaluation in Advanced Lung (IDEAL) 1 and 2 trials. IDEAL 1 was a multi-center, international, randomized, controlled study that looked at patients with locally advanced or metastatic NSCLC who failed standard platinum based therapy. Patients were randomized to receive either 250 or 500mg of oral daily gefitinib. Disease related symptoms and quality of life were assessed every week and every month respectively. End points included objective response rates (ORR), progression free survival (PFS), and overall survival (OS). The ORR were 18.4% and 19%, PFS were reported as 2.7 months and 2.8 months, and overall median survival was 7.6 and 8.0 months respectively. None of these were statistically significant. However, the gefitinib arm was associated with an improvement in disease related symptoms and quality of life. PFS was noted to be twice as long in patients who experienced an improvement in their disease related symptoms compared to those who did not.
The IDEAL 2 trial confirmed data from IDEAL 1. Based on this phase II trial, gefitinib gained the FDA approval. The drug was studied in 216 patients with NSCLC who previously failed platinum based and docetaxel chemotherapy. The response rate, defined as at least a 50% tumor shrinkage lasting at least one month, was calculated to be 10%. The higher gefitinib dose did not seem to provide a better response but 500mg seemed to be associated with more drug related toxicities.
The response rates appeared to be variable in certain subgroups of patients. For example, the highest response rates were seen in women (17%) and patients with adenocarcinoma. The lowest responses, in contrast, were seen in men (5%) and smokers. A significant improvement in survival was noted in both trials, in those patients who had treatment related symptom improvement compared to those who did not (8.1 months versus 3.7).
Preclinical data showed enhancement of cytotoxicity for a variety of chemotherapeutic agents when combined with gefitinib. Two large randomized controlled studies of the drug as first line treatment in combination with conventional platinum based chemotherapy – combination of carboplatin /paclitaxel /gefitinib or gemcitabine (Gemzar®) /cisplatin / gefitinib – compared to the cytotoxic chemotherapy alone did not show a benefit. These were disappointing results and not anticipated.
In May 2003, gefitinib was reviewed and approved under the United States Food and Drug Administration accelerated approval regulations program. The approval clearly states that 250mg of oral gefitinib is accepted as monotherapy for patients with locally advanced or metastatic NSCLC after failure of both platinum and docetaxel chemotherapies. A tyrosine kinase inhibitor that acts on the EGFR such as gefitinib is the first drug of its kind to receive approval in lung cancer.
The most concerning side effect of gefitinib emerged just after the FDA recommended it to be approved for its new indication. Several reports from Japan described the occurrence of a sometimes-fatal interstitial pneumonitis. Due to this troubling experience, the FDA investigated the matter further and concluded that the incidence of this complication is about 1% in the Japanese population and 0.3% in the US. Furthermore, only one third of these rare cases are fatal. Although serious, the FDA believes that the benefits of this drug outweigh even these risks. Other more common side effects include diarrhea (48), rash (43%), acne (25%), dry skin (13%) and nausea (13%). These side effects generally occur in the first month of treatment and are usually mild.
The company who made gefitinib will sponsor three more post marketing studies assessing gefitinib's clinical benefit. One trial will look to see if survival is prolonged, when compared to placebo, in patients whose tumors are resistant to two prior chemotherapies. A second trial will compare gefitinib to the standard of care second line chemotherapy for NSCLC in patients previously treated with only one regimen. Finally, the third trial will evaluate gefitinib's ability to reduce cancer related symptoms in patients whose cancer is resistant to all available chemotherapy. We eagerly await these results.