Select clinical trials of erlotinib (OSI-774) in non-small-cell lung cancer with emphasis on phase III outcomes

Abstract

Lung cancer is primarily diagnosed during the advanced stage of disease, at which stage treatment options are severely limited. It is primarily for this reason that lung cancer carries a higher mortality rate than breast, prostate, and colon cancers combined. Traditional treatments for metastatic non-small-cell lung cancer (NSCLC) include chemotherapy; however, this approach, although the standard of care, is toxic and nonspecific, thereby rendering treatment inaccessible to those with a poor performance status. Alternatively, there are recent emerging treatment options that involve inhibiting specific molecular targets. This includes the epidermal growth factor receptor (EGFR), which is known to potentiate tumor cell proliferation and metastases, while also attenuating apoptosis. This target is especially important because approximately 85% of all lung cancers are categorized as NSCLC, which expresses EGFR at a rate of 40%-85%. In addition, newly developed EGFR-specific tyrosine kinase inhibitors (TKIs) have been used in clinical trials with encouraging results. To date, gefitinib and erlotinib (OSI-774; Tarceva) are the most studied of the EGFR TKIs for the treatment of NSCLC. In this article we have focused on 3 recently completed trials involving erlotinib as monotherapy (BR.21 study) or in combination with standard chemotherapeutic regimens (TALENT and TRIBUTE trials) for the treatment of NSCLC. When used in combination with carboplatin/paclitaxel (TALENT) or cisplatin/gemcitabine (TRIBUTE), erlotinib was found not to improve survival. These results contrast with what would be predicted from preclinical data outcomes, but they complement recent phase III reports involving similar combinations with gefitinib. Subset analysis of the TRIBUTE trial revealed that never-smokers had the greatest survival benefit. Conversely, erlotinib has exhibited overall survival benefits when used as monotherapy (BR.21 study). In addition, recent information involving mutations within the kinase domain of the EGFR may be implicated in the response seen with EGFR TKIs in recent trials.