Emerging Role of Erlotinib (OSI-774) in Non–Small-Cell Lung Cancer

Abstract

Erlotinib (OSI-774; Tarceva™) is a novel, specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), recently approved by the US Federal Drug Administration for patients with locally advanced or metastatic non–small-cell lung cancer (NSCLC) after failure of ≥ 1 prior chemotherapy regimen. The approval was based on the improvement in survival with erlotinib assessed in a randomized, double-blind, placebo-controlled trial (BR.21).1 The median overall survival was 6.7 months in the erlotinib group compared with 4.7 months in the placebo group (hazard ratio, 0.73; 95% CI, 0.61-0.86; P < 0.001). The most common adverse events in patients receiving erlotinib were rash and diarrhea. Grade 3/4 rash and diarrhea occurred in 9% and 6%, respectively. This supplement describes the data available to date on erlotinib in NSCLC. The interest of clinicians and basic scientists was sparked by the impressive response to EGFR TKIs in some patients with NSCLC. This led to the discovery of EGFR mutations in the tyrosine kinase domain that appear to predict response with these agents.2,3 Although the data are of great interest, EGFR mutations do not fully explain the clinical benefit that patients derive from EGFR-targeted therapies. Nevertheless, this is an exciting and promising development in the history of treating lung cancer that demands further investigation, as described by Perea and Hidalgo. It is only a matter of time until we will be able to prescribe tailor-made therapies for our patients with lung cancer. Calvo and Rowinsky have put this data into perspective. Patients who have the mutation are most likely to respond to treatment and are likely to be female, lifetime nonsmokers, of Asian ethnic origin, and have adenocarcinoma histology. Treatment with erlotinib or gefinitib should not be withheld from patients who do not match this profile; although survival benefits have been noted in subgroups of patients who do not have mutations, the magnitude of benefit may be reduced, as discussed in the article by Herbst and Sandler. Performance status (PS) is the single most important prognostic indicator of survival in lung cancer, yet there has been no standard of care for patients with poor PS. Although these patients do derive benefit from chemotherapy, erlotinib has presented evidence of significant improvement in survival in the BR.21 trial.1 Of the 488 patients treated with erlotinib, 26% had PS 2 and 9% had a PS of 3. A trial of erlotinib versus chemotherapy has been initiated in this subset of patients. Perez-Soler has reviewed phase II data with erlotinib. He states that it is an active and well-tolerated agent in second- and thirdline settings. Among pretreated patients, erlotinib response does not correlate with the number of previous chemotherapy regimens, but patients who had received docetaxel as second-line therapy had a higher objective response rate. In patients with bronchoalveolar carcinoma (BAC), erlotinib response correlates most highly with a history of nonsmoking and adenocarcinoma histology with BAC features. Seven of 8 responders had activating mutations of the EGFR. Among elderly untreated patients without BAC, the erlotinib response rate to date is 13.3%. Anecdotal reports of swift and durable responses in patients with BAC treated with EGFR TKIs prompted further investigation. Trials of single-agent gefinitib and erlotinib in patients with BAC have yielded promising results,4,5 as described by Patel. One third of patients with BAC never smoked, compared with approximately 10% of other lung cancer histologies, and BAC occurs more frequently in women than in men. Patients diagnosed with early-stage BAC live longer than patients with other histologic subtypes of NSCLC. When BAC becomes metastatic to extrapulmonary sites, its prognosis is similar to that of general adenocarcinoma. Targeted agents, primarily the EGFR inhibitors, have led to a new era in the treatment of patients with NSCLC. Qualitative and quantitative survival benefit has been demonstrated with erlotinib as a single agent for patients with advanced NSCLC. The discovery of mutations in the EGFR has opened the door to proper selection of patients for therapy with EGFR inhibitors.