Patients with advanced non-small cell lung cancer (NSCLC) who try standard chemotherapy generally live a few months longer than those who opt instead for supportive care.
A potential alternative to standard chemotherapy is the drug erlotinib (Tarceva). It is one of the so-called targeted drugs that more specifically targets cancer cells and so does less damage to normal cells. Erlotinib, a pill, targets a protein called the epidermal growth factor receptor (EGFR). EGFR, which helps cells to divide, is found at abnormally high levels on the surface of many types of cancer cells, including many cases of non-small cell lung cancer. Researchers think that by interfering with EGFR, erlotinib may keep tumors from growing.
In 2004, researchers with a phase II trial involving previously treated NSCLC patients reported that tumors in 12 percent of the participants responded to treatment with erlotinib. It was unclear, however, whether erlotinib helped the patients live any longer.
The phase III trial described here was designed to see if erlotinib could prolong survival among advanced NSCLC patients for whom standard chemotherapy was no longer working.
Between August 2001 and January 2003, researchers enrolled 731 patients with advanced NSCLC whose disease had progressed after one or two courses of chemotherapy. The patients were divided randomly into two groups. One group (488 patients) received erlotinib and the other group (243 patients) received a placebo. The study was double-blinded, meaning that neither the patients or their doctors knew which treatment the patients were getting.
Of the 731 total patients, 472 agreed to allow researchers to collect and analyze samples of their tumors (called tissue banking). The goal: to see whether survival and tumor responsiveness could be associated with particular patterns of EGFR expression, the molecule targeted by erlotinib. (EGFR appears on many cells, not just cancer cells, and it doesn't appear on the cancer cells of every patient.) Findings from the molecular analysis were reported separately in the same journal issue; the lead author was Ming-Sound Tsao, M.D., of the University of Toronto in Ontario (see the journal abstract).
The clinical trial's principal investigator was Frances A. Shepherd, M.D., also of the University of Toronto. The study was coordinated by the National Cancer Institute of Canada Clinical Trials Group and is commonly referred to as the BR.21 trial (see the protocol summary).
The median survival among patients who took erlotinib was 6.7 months compared to 4.7 months for those on placebo. At one year, 31 percent of the patients taking erlotinib were still alive compared to 22 percent of those taking the placebo.
The time it took before the cancer progressed was also longer in the erlotinib group - 2.2 months compared to 1.8 months in the placebo group. All these findings were statistically significant. In addition, more patients receiving erlotinib reported improvements in key symptoms of advanced NSCLC, such as cough, pain, and dyspnea (difficulty breathing).
More than half of those who had contributed tissue samples had tumors that expressed EGFR. This study suggested that they responded better to erlotinib (11 percent versus 4 percent of patients whose tumors did not express EGFR). Those whose tumors had more copies of the EGFR molecule also responded best. Earlier studies had suggested that specific mutations of EGFR might be associated with a better response to erlotinib, but the BR.21 trial didn't confirm this finding.
Researchers did find that certain subsets of patients were most likely to respond to erlotinib: Asians; women; patients with adenocarcinoma; and those who had never smoked. These results confirmed those of numerous other studies.
Patients receiving erlotinib experienced more toxic side effects. For example, 9 percent of the erlotinib group suffered from moderate-to-serious rash while none of the placebo group did. Overall, 5 percent of patients stopped taking erlotinib because of toxic effects as compared to 2 percent of those taking placebo.
Results from the BR.21 trial were originally presented at the 2004 meeting of the American Society of Clinical Oncology.
A quality of life analysis from this study was subsequently published in the Aug. 20, 2006, issue of the Journal of Clinical Oncology (see the journal abstract). This analysis found that erlotinib improved tumor-related symptoms and important aspects of the patients' quality of life.
In a related editorial, James H. Doroshow, M.D., of the National Cancer Institute's Division of Cancer Treatment and Diagnosis, noted that the tissue samples were only collected from about half of all the study's patients. This "clearly reduced the strength of the conclusions it was possible to draw" from the molecular analysis part of the study.
Also, the researchers didn't take tissue samples in a standardized way - sometimes they took samples from the initial surgery and sometimes from subsequent biopsies. This makes it harder to reach reliable conclusions about which EGFR characteristics make tumor cells most responsive to erlotinib.
This is an important study because "it is the first EGFR-targeted therapy to show a significant survival benefit" in this group of patients, said Shepherd. These patients "now have an option to improve survival with minimal toxicity."