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Thoracic Oncology – Respiratory Diseases Division
Faculty of Medicine
Université de la Méditerranée – Assistance Publique Hôpitaux de Marseille
Epidermal growth factor receptor (EGFR) inhibitors became the focus of some attention in the management of nonsmall-cell lung cancer (NSCLC) patients for at least three reasons. First, despite therapeutic progresses, NSCLC remains, worldwide, a leading cause of cancer-related death. Secondly, despite a survival improvement partially related to third-generation drugs (vinorelbine, gemcitabine, paclitaxel and docetaxel), a therapeutic plateau has been reached, highlighting the need for new drugs and new strategies.(1) Thirdly, EGFR overexpression is frequent in NSCLC (45–70%),(2) and patients with tumour overexpressing EGFR experienced a shorter survival.(3) Thus, EGFR represents both a specific and a relevant target.
EGFRs belong to a superfamily of four receptors (c-ERBB1 or EGFR, c-ERBB2 or HER2, c-ERBB3 and c-ERBB4). These receptors possess an extracellular ligand-binding domain, a transmembrane domain and an intracellular tyrosine kinase (TK) domain (apart from c-ERBB3). The EGFR has several ligands; after ligand binding, the EGFR forms homodimers or heterodimers, then tyrosine autophosphorylation occurs, which leads to intracellular responses affecting cell survival, angiogenesis, cell proliferation and cell differentiation. Considering the presence of both an extracellular and an intracellular domain, two different strategies have been explored to block the EGFR: first, by targeting the extracellular domain with a monoclonal antibody, cetuximab (C225), in the same way as herceptin targets HER2 receptors; secondly, by targeting the intracellular TK domain with EGFR-TKIs, such as gefitinib and erlotinib.
Monoclonal antibody: cetuximab
Few data have been published to date regarding cetuximab for the management of NSCLC. A phase II study of cetuximab as salvage therapy in 66 unselected patients has been presented at the ASCO meeting 2005 and reported a response rate (RR) of 3.3% with a one-year survival (1-YS) of 43%.(4)
A phase II randomised study of cetuximab in combination with cisplatin and vinorelbine versus chemotherapy alone as first-line treatment of patients with EGFR-expressing advanced NSCLC was presented in 2004.(5) Safety data showed that cetuximab could be added to chemotherapy without major toxicity. Data on response (31.7 versus 20%) and survival (time to progression, 4.7 versus 4.2 months) have to be extended to a more important population of patients. A phase III study is ongoing.
EGFR tyrosine kinase inhibitors: gefitinib and erlotinib
Salvage therapy (second- or third-line therapy)
Two phase II studies on gefitinib in pretreated advanced NSCLC patients (IDEAL 1 and 2 studies)(6,7) showed encouraging results (see Table 1), leading to gefitinib approval in several countries. In addition, a phase II study of gefitinib versus docetaxel as second-line chemotherapy (SIGN study) showed comparable results for both drugs (see Table 1).(8) However, a recently presented randomised phase III study of gefitinib 250mg versus placebo (ISEL study)(9) in pretreated advanced NSCLC patients showed no significant survival advantage for patients treated with gefitinib over placebo (see Table 1).
Conversely, in a similarly designed randomised phase III study in pretreated patients (BR21 trial),(10) erlotinib 150mg demonstrated a significant survival advantage over placebo (see Table 1). Therefore, erlotinib is now registered in several countries for these patients.
First-line therapy in combination with platinum-based chemotherapy
When combined with first-line platinum-based chemotherapy, EGFR-TKIs failed to provide a significant survival benefit. Indeed, four large randomised trials including more than 4,000 NSCLC patients were conducted (INTACT studies 1 and 2, TRIBUTE and TALENT studies). All these four studies concluded to the absence of survival advantage for EGFR-TKIs when added to first-line chemotherapy in unselected NSCLC patients (see Table 2).(11–14)
First-line therapy as single agent
Studies focusing on EGFR-TKIs as first-line treatment have recently been reported. For example, Giaccone et al reported a phase II study of erlotinib as first-line and showed a 24.5% RR.(15) Two similar studies on patients treated with gefitinib showed comparable results with a 26.5–33.3% RR.(16,17)
Sequential studies of EGFR-TKIs following chemotherapy have been planned after combination studies suggested that maintenance may help after termination of chemotherapy. However, the SWOG 0023 randomised trial on gefitinib versus placebo after chemoradiotherapy for inoperable stage III NSCLC was closed early, giving disappointing results. Indeed, patients receiving gefitinib experienced a lower survival over placebo (median survival of 19 versus 29 months, p=0.09).(18) Other studies are still ongoing.
EGFR-TKIs showed a good toxicity profile, with skin rash and diarrhoea as major but almost always manageable side-effects, occurring in approximately 40% of patients.
The major drawback of previously discussed studies is a lack of patient selection, based on EGFR expression or any other marker of efficacy, which may have been responsible for the lack of positive outcomes.
A number of clinical characteristics have been reported to predict sensitivity to EGFR-TKIs: female gender, absence of a smoking history and adenocarcinoma or bronchioloalveolar histological subtype.(19) Race has also been shown to have an impact on sensitivity to treatment, as East Asians derive much more benefit from treatment than Caucasians.(20) Interestingly, the difference in EGFR-TKI sensitivity between smokers and nonsmokers may be due to pharmacokinetic differences. For example, in a pharmacokinetic subset analysis of patients in the BR21 trial, lower trough level concentration of erlotinib were reported for patients with a current smoking history when compared with nonsmokers. (21) The study of the EGFR pathways may also provide the tool for patient selection. While EGFR expression by immunohistochemistry is relatively easy, overexpression of EGFR has not been correlated with in-vitro or in-vivo sensitivity to EGFR-TKIs. Conversely, EGFR gene mutations within exons 18–21 have been reported to correlate with response to EGFR-TKIs.(22,23) Mutations in EGFR are found more frequently in patients with adenocarcinomas, nonsmokers, patients of Asian ethnicity and females. However, it should be noted that a substantial proportion of patients responding to EGFR-TKIs do not present with EGFR gene mutations. More recently, new data emerged on the relationship between EGFR gene copy number and response to EGFR-TKIs.(24,25)
Inclusion of patients in well-designed clinical trials with a concurrent collection of pathological tissue for molecular analysis should be an objective of all future trials on EGFR-TKIs in the treatment of NSCLC.
In addition, newly designed trials include either a clinical or a biological screening of patients. For example, the SWOG conducted a study of gefitinib as first-line treatment for bronchioloalveolar cancer, reporting a 21% RR and a 50% 1-YS.(26) In the same way, a trial of gefitinib as first-line therapy of adenocarcinoma in never-smokers showed an impressive 69% of partial response with an estimated 73% 1-YS.(27) The clinical selection is also being used in several ongoing studies: The Duke Comprehensive Cancer Center is conducting a study with celecoxib and gefitinib in former smokers, the Cancer and Leukemia Group B (CALGB) will conduct a trial in never or former smokers with adenocarcinoma or bronchioloalveolar carcinoma (CALGB30406), and a phase II study of female never or former smokers with adenocarcinoma is being conducted by the Dana Farber Cancer Institute.
On the other hand, a biological selection based on the presence of EGFR mutations is being used in other studies: the West Japan Thoracic Oncology Group is conducting a trial with gefitinib as first-line therapy in patients carrying the EGFR gene mutation, while a similarly designed study called TARGET is being conducted in the USA, and a Spanish study will explore the efficacy of erlotinib in NSCLC patients presenting with adenocarcinoma plus an EGFR gene mutation. Finally, new agents targeting EGFR receptors as well as HER2 and VEGF, and combination of EGFR-TKIs with other target therapies, are under investigation.
EGFR inhibitors are new anticancer agents available for the management of NSCLC patients. To date, evidence-based data strongly support the use of erlotinib as salvage therapy for refractory or relapsing patients after platinum-based chemotherapy. In addition, evidence strongly suggests that erlotinib and gefitinib might be useful as single-agent first-line therapy for clinically (never- smokers?; bronchioloalveolar pathological subtypes?) or biologically (EGFR gene mutation?; high EGFR gene copy number?) selected NSCLC patients. Several ongoing trials are designed to clarify how to integrate these agents in daily practice.
American Society of Clinical Oncology
US National Cancer Institute
2006 American Association for Cancer Research meeting. 1–5 April 2006, Washington DC, USA
2006 American Society of Clinical Oncology meeting. 2–6 June 2006, Atlanta, Georgia, USA