Use of Erlotinib or Gefitinib as Initial Therapy in Advanced NSCLC
Use of Erlotinib or Gefitinib as Initial Therapy in Advanced NSCLC
ABSTRACT: Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR), such as erlotinib (Tarceva) and gefitinib (Iressa), have shown remarkable activity in a portion of patients with non–small-cell lung cancer (NSCLC). Based on a large randomized controlled trial showing a survival benefit compared with placebo, erlotinib gained US Food and Drug Administration approval for use in previously treated patients with NSCLC. However, its use in the firstline setting has been largely experimental. Recently, a large phase III randomized controlled trial demonstrated the superiority of first-line gefitinib therapy compared to combination chemotherapy in a clinically selected population consisting of Asian patients with adenocarcinoma and a light smoking history. This result was even more dramatic in the subset of patients whose tumors carried a mutation in the EGFR gene. Currently, randomized phase III trials of erlotinib as initial treatment of patients with EGFR mutant lung cancer are ongoing. In the setting of these recent developments, a review of the data regarding the use of erlotinib or gefitinib as initial therapy in the treatment of NSCLC is warranted. Currently active trials are referenced using their ClinicalTrials.gov identifier.
The development of tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) has revolutionized the care of patients with non–small-cell lung cancer (NSCLC). In 2004, erlotinib (Tarceva) received US Food and Drug Administration (FDA) approval for the treatment of previously treated NSCLC. Gefitinib (Iressa) was initially approved to treat NSCLC in May 2003, but in June 2005, the FDA approved new labeling that limited the approval, ie, only for patients who are currently benefiting (or have previously benefited) from this agent. Outside the United States, both drugs are used widely.
EGFR is a member of the HER/ErbB family of membrane-bound receptors, and it plays a role in signal transduction of extracellular ligands including transforming growth factor alpha (TGF-α), amphiregulin, and epidermal growth factor (EGF).1 EGFR is overexpressed in numerous epithelial and neuroectodermal malignancies, a finding that initially motivated the exploration of EGFR as a novel therapeutic target. Erlotinib (formerly named OSI-774) and gefitinib (formerly named ZD1839) are small molecules that were designed to selectively inhibit the phosphorylation of the EGFR intracellular kinase domain. Phase I studies identified diarrhea and rash as dose-limiting toxicities with once daily oral dosing, and occasional dramatic responses were observed in some patients.2,3
Gefitinib and Erlotinib in Previously Treated Patients
Initial phase II experience with gefitinib and erlotinib in previously treated patients with advanced NSCLC demonstrated promising antitumor activity with response rates of 12% to 19%.4-6 Gefitinib initially gained preliminary FDA approval in previously treated patients based on the phase II Iressa Dose Evaluation in Advanced Lung Cancer 2 (IDEAL-2) trial, demonstrating symptomatic improvement in 43% of patients receiving 250 mg daily, with a response rate of 12%.5 Erlotinib was then FDA approved in previously treated patients, based on the phase III randomized placebo-controlled BR.21 trial, demonstrating an overall survival advantage in the erlotinib arm (6.7 vs 4.7 months) with a response rate of 8%.7 However, the postapproval phase III placebo-controlled study of gefitinib, the Iressa Survival Evaluation in Lung Cancer (ISEL) trial, was a negative study showing only a small difference in overall survival between the experimental arm and placebo (5.6 vs 5.1 months, P = .087).8 Interestingly, the BR.21 study showed a statistically significant association between response rate and four clinical factors: Asian race, adenocarcinoma histology, negative smoking history, and female gender. The association of these factors with antitumor activity was similarly found in several studies of gefitinib,5,8 which also noted particular activity against adenocarcinomas of the bronchioloalveolar carcinoma (BAC) subtype.9
An important feature of initial studies of erlotinib efficacy was that while the overall response rate was low, patients who did respond often had dramatic, rapid, and sustained improvement in their tumor burden.10 Several groups performed analyses of tumor samples from patients demonstrating sensitivity to erlotinib and gefitinib, with nucleotide sequencing of their target, EGFR. These tumors were found to commonly carry mutations in the tyrosine kinase domain of the EGFR gene, which were absent in tumors resistant to these agents11-13—a finding analogous to the presence of KIT mutations in imatinib (Gleevec)-sensitive gastrointestinal stromal tumors. Furthermore, these EGFR mutations were found to be more prevalent in patients with the clinical features associated with TKI sensitivity: Asian race, adenocarcinoma histology, negative smoking history, and female gender. The importance of mutations in the EGFR gene is further highlighted by the finding of highly prevalent acquired mutations in EGFR exon 20 in tumors that have developed resistance to EGFR TKIs.14,15
Erlotinib and Gefitinib as First-Line Agents
Given the efficacy of EGFR TKI therapy in previously treated patients, many groups have explored the use of erlotinib and gefitinib in the firstline setting. In the ensuing sections, we will discuss the first-line phase II experience with these agents in three different groups: patients unselected for TKI sensitivity, patients clinically selected for TKI sensitivity, and patients molecularly selected for TKI sensitivity. We will then discuss the recent randomized phase III experience. A summary of these studies can be found in Table 1.
Untreated Patients Unselected for TKI Sensitivity
Initial trials of first-line EGFR TKI therapy in unselected patients demonstrated modest efficacy at best. A phase II trial of erlotinib by Giaccone et al in 58 patients showed a response rate of 23%, though with a median progression-free survival of only 2.8 months.16 This study found that response was significantly associated with histology and smoking status, and noted that 4 of 7 patients with EGFR mutations responded. But another early phase II trial showed a much lower response rate of 5% in unselected patients treated with gefitinib,17 and a more recent trial has shown a borderline response rate of 15%, with responses noted in 3 of 4 patients with EGFR mutations.18
The relatively mild toxicity profile of EGFR TKI therapy has led to interest in using these agents as first-line therapy in patients who are elderly or have a poor performance status (PS). Two single-arm phase II studies of erlotinib, one in patients aged 70 and older and one in patients with a PS of 2, demonstrated response rates of 8% and 10%, respectively.19,20 The former study found a response rate of only 33% in 9 patients with EGFR mutations, though these patients did have a prolonged median progressionfree survival (> 15 months).
Two other phase II studies have evaluated first-line TKIs randomized against chemotherapy as a control. In the Iressa in NSCLC Versus Vinorelbine Investigation in the Elderly (INVITE) trial,21 untreated elderly patients (aged 70 years or older) were randomized to gefitinib vs vinorelbine, and the treatments were found to be statistically similar, with a response rate of only 3% for gefitinib. Lilenbaum et al compared erlotinib to combination carboplatin and paclitaxel in 52 patients with a PS of 2 and found a 4% response rate for erlotinib, with better survival in the chemotherapy arm (9.5 vs 6.6 months).22EGFR mutation status was available for 21 of these patients, with 5 testing positive, but all were in the chemotherapy arm. In summary, the available data indicate that conventional chemotherapy remains the preferred initial therapy for unselected patients, even those with a borderline PS.
A potential role for EGFR TKIs in unselected patients unfit for chemotherapy is currently being studied in a randomized phase II trial of first-line erlotinib vs placebo in this population (Tarceva or Placebo in Clinically Advanced Non Small Cell Lung Cancer, or TOPICAL; ClinicalTrials.gov identifier NCT00275132).