Tarceva® (erlotinib tablets)
Tarceva is a small molecule human epidermal growth factor type 1/epidermal growth factor receptor (HER1/EGFR) inhibitor which has demonstrated, in a Phase III clinical trial, an increased survival in advanced non-small cell lung cancer (NSCLC) patients. In a Phase III trial, Tarceva has also shown an improvement in overall survival when added to gemcitabine chemotherapy as initial treatment for pancreatic cancer.
Status
In November 2004, the U.S. Food and Drug Administration (FDA) approved Tarceva for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen. Tarceva was approved under the FDA's Pilot Program for Continuous Marketing Applications, a program designed for investigational products, such as Tarceva, that have been given Fast Track status and that have demonstrated significant promise in clinical trials as a therapeutic advance over available therapy for a disease or condition.
The FDA based its approval for Tarceva in NSCLC on results from a randomized double-blind, placebo-controlled pivotal Phase III trial of patients with second- and third-line advanced NSCLC. The trial included 731 patients for whom one or more chemotherapy regimens had failed. Tarceva met its primary endpoint of improving overall survival (hazard ratio = 0.73). In addition to demonstrating a 42 percent improvement in median survival (6.7 versus 4.7 months), 31.2 percent of patients receiving Tarceva in the study were alive after one year versus 21.5 percent in the placebo arm. Tarceva also met all secondary endpoints of the trial, including delaying time to symptom deterioration, improving progression-free survival, and increasing tumor response rate.
In November 2005, the FDA approved Tarceva in combination with gemcitabine chemotherapy for the treatment of locally advanced, inoperable or metastatic pancreatic cancer in patients who have not received previous chemotherapy. Tarceva became the first new therapy in nine years approved for pancreatic cancer.
The FDA based its approval decision for Tarceva in this indication on results from a randomized double-blind, placebo-controlled Phase III clinical study of Tarceva, in combination with gemcitabine chemotherapy in 569 patients with unresectable locally advanced or metastatic pancreatic cancer. The study met its primary endpoint of improving overall survival by 23 percent (hazard ratio = 0.81). After one year, 24 percent of patients receiving Tarceva plus gemcitabine were alive compared to 19 percent of patients receiving gemcitabine plus placebo. A statistically significant improvement in progression-free survival (hazard ratio = 0.76) also was demonstrated.
Safety
The safety profile of Tarceva is well established. In the pivotal Phase III study in NSCLC, BR.21, the most common adverse reactions in patients receiving Tarceva were rash and diarrhea. Grade 3/4 rash and diarrhea occurred in 9 and 6 percent of Tarceva-treated patients, respectively. Rash and diarrhea each resulted in discontinuation of 1 percent of Tarceva-treated patients. Dose reduction for rash and diarrhea was needed for 6 and 1 percent of patients, respectively. Historically, there have been infrequent reports of serious interstitial lung disease (ILD), including fatalities, in patients receiving Tarceva for treatment of NSCLC or other advanced solid tumors. In the pivotal trial in NSCLC, severe pulmonary reactions, including potential cases of interstitial lung disease, were infrequent (0.8 percent) and were equally distributed between treatment arms. The overall incidence of ILD in Tarceva-treated patients from all studies was approximately 0.7 percent.
In the pivotal Phase III study in pancreatic cancer, Trial PA3, the most common adverse events reported were fatigue, rash, nausea, anorexia and diarrhea. Rash was reported in 69 percent of patients who received Tarceva plus gemcitabine and in 30 percent of patients who received gemcitabine plus placebo. Diarrhea was reported in 48 percent of patients who received Tarceva plus gemcitabine and in 36 percent of patients who received gemcitabine plus placebo. Two percent of the patients discontinued Tarceva because of rash and 2 percent because of diarrhea. In addition, severe and potential fatal adverse events included interstitial lung disease-like complications, myocardial infarction or ischemia, cerebrovascular accident, and microangiopathic hemolytic anemia with thrombocytopenia.
Proposed Mechanism of Action
Tarceva is a small molecule designed to target the human epidermal growth factor receptor (HER1) pathway, which is one of the factors critical to cell growth in numerous cancers, including non-small cell lung and pancreatic. HER1, also known as EGFR, is a component of the HER signaling pathway, which plays a role in the formation and growth of non-small cell lung and pancreatic cancers. Tarceva is designed to inhibit the tyrosine kinase activity of the HER1 signaling pathway inside the cell.
Non-Small Cell Lung Cancer
According to the World Health Organization, there are more than 1.2 million cases worldwide of lung and bronchial cancer each year, causing approximately 1.1 million deaths annually. It is estimated that more than 172,000 people will be diagnosed with lung cancer in the United States in 2005. According to the American Cancer Society, lung cancer is the single largest cause of cancer deaths in the United States, and is responsible for nearly 28 percent of cancer deaths in this country. NSCLC is the most common form of the disease and accounts for almost 80 percent of all lung cancers.
Pancreatic Cancer
According to the World Health Organization, more than 216,000 people worldwide are diagnosed each year with pancreatic cancer. The American Cancer Society predicts that in 2005 about 32,180 people in the United States will be diagnosed with pancreatic cancer and about 31,800 will die of the disease. Although pancreatic cancer accounts for two percent of new cancer cases in the United States, it is the fourth leading cause of all cancer deaths. Most pancreatic tumors originate in the exocrine duct cells or in the cells that produce digestive enzymes (acinar cells). Called adenocarcinomas, these tumors account for nearly 95 percent of pancreatic cancers.