Targeted therapies inhibiting the epidermal growth factor receptor(EGFR) have been introduced in the treatment of patients with advancednon–small-cell lung cancer (NSCLC). Many inhibitors of theEGFR have been developed, targeting either the extracellular receptordomain with antibodies or the intracellular tyrosine kinase bindingdomain with small molecules. The tyrosine kinase inhibitor (TKI)gefitinib (Iressa) was the first targeted drug to be registered for thetreatment of NSCLC after failure of chemotherapy. Given concurrentlytogether with platinum combination chemotherapy both TKIs gefitiniband erlotinib (Tarceva) failed to increase activity. Sequential targetedtherapy after chemotherapy is currently being investigated further. Studieswith the monoclonal antibody cetuximab (Erbitux) combined withchemotherapy are ongoing. Side effects of the small molecules aremainly skin rash and diarrhea, whereas the antibodies do not give diarrhea.Selection of patients, based on molecular markers and patientcharacteristics, has become an important issue for the further developmentof these drugs, given there is activity in a relatively small group ofpatients with NSCLC. Newer drugs inhibiting more than one receptorpathway are being investigated in order to find activity in a broadergroup of patients.
Targeted therapies inhibiting the epidermal growth factor receptor (EGFR) have been introduced in the treatment of patients with advanced non–small-cell lung cancer (NSCLC). Many inhibitors of the EGFR have been developed, targeting either the extracellular receptor domain with antibodies or the intracellular tyrosine kinase binding domain with small molecules. The tyrosine kinase inhibitor (TKI) gefitinib (Iressa) was the first targeted drug to be registered for the treatment of NSCLC after failure of chemotherapy. Given concurrently together with platinum combination chemotherapy both TKIs gefitinib and erlotinib (Tarceva) failed to increase activity. Sequential targeted therapy after chemotherapy is currently being investigated further. Studies with the monoclonal antibody cetuximab (Erbitux) combined with chemotherapy are ongoing. Side effects of the small molecules are mainly skin rash and diarrhea, whereas the antibodies do not give diarrhea. Selection of patients, based on molecular markers and patient characteristics, has become an important issue for the further development of these drugs, given there is activity in a relatively small group of patients with NSCLC. Newer drugs inhibiting more than one receptor pathway are being investigated in order to find activity in a broader group of patients.
Lung cancer is the leading cause of cancer-related death, with 1.2 million cancer deaths due to lung cancer in the year 2002 in the western world. More than 50% of non-small-cell lung cancer (NSCLC) patients are candidates for systemic treatment with chemotherapy, either for advanced disease or as adjuvant or neoadjuvant treatment in addition to local therapy in earlier stages. Chemotherapy has, however, modest activity in NSCLC. In the past few years several new drugs that more specifically work on cancer cell targets have shown activity in NSCLC. The most-investigated target is the epidermal growth factor receptor (EGFR). This receptor is a member of the ErbB family of transmembrane tyrosine kinase receptors, which includes ErbB1 (or HER1, or EGFR), ErbB2 (or HER2/neu), ErbB3 (or HER3), and ErbB4 (or HER4). The expression of EGFR is common in a number of normal epithelial tissues and expression of EGFR is elevated in several solid tumors. In NSCLC, overexpression of EGFR has been reported to be present in over 50% of cases in several series. In addition to this, several retrospective studies have identified the expression of this receptor as a negative prognostic factor in patients with resected early NSCLC. Clinical Studies With EGFR Inhibitors in NSCLC Several EGFR inhibitors have been developed in recent years; they can mainly be categorized into two classes: monoclonal antibodies to the extracellular domain of the EGF receptor, or small molecules which are inhibitors of the intracellular tyrosine kinase (TKI) domain, interfering with autophosphorylation by ATP. Other molecules, however, have also been developed, including vaccines.[ 4] Single Agents
Combinations With Chemotherapy
The oral EGFR targeting the TKIs gefitinib and erlotinib have both been tested in several large randomized controlled trials in combination with platinum doublet chemotherapy combinations. These studies all failed to show a benefit of the concomitant use of these agents in over 4,000 patients with advanced NSCLC.[34-37] In none of these studies were patients selected based on EGFR expression or any other marker of efficacy; this lack of patient selection may have caused the lack of positive outcome. Interestingly, however, the time to progression and survival curves suggest that maintenance EGFR inhibition may be of help after termination of chemotherapy. In the initial part of the survival curves, the EGFR TKI arms of all these studies do worse than the placebo arms. This is unlikely due to toxicity, as even the higher doses of these drugs are relatively well tolerated in combination with chemotherapy. EGFR inhibitors act mainly by reducing proliferation in wild-type EGFR tumor cells; proliferating tumor cells are those most affected by chemotherapy, therefore an antagonistic effect between EGFR TKIs and chemotherapy is plausible. Based on these considerations, sequential studies of EGFR TKIs (both gefitinib and erlotinib) following chemotherapy have been planned or are presently accruing; these studies investigate whether a TKI may increase outcome in patients who were not progressing on chemotherapy. Cetuximab given at 400 mg/m2 on day 1 and at 250 mg/m2 weekly thereafter has been combined with cisplatin at 80 mg/m2 on day 1 and vinorelbine at 25 mg/m2 on day 1 and 8, in a randomized phase II study. A total of 101 patients whose tumors expressed EGFR were included. At a preliminary assessment the response rate was 31.7% in the cetuximab arm and 20% in the chemotherapy alone arm. Based on these results, a large phase III randomized study has recently been launched to compare cisplatin/vinorelbine to the same chemotherapy in combination with cetuximab. Furthermore, there are two ongoing randomized phase II studies in the US that use the chemotherapy regimens carboplatin/ paclitaxel and cisplatin/gemcitabine with or without cetuximab. In a phase I/II trial of advanced NSCLC patients treated with one prior regimen were given erlotinib and bevacizumab (Avastin), a recombinant anti-VEGF monoclonal antibody.[ 39] Both agents could be given at the full dose of 150 mg/d of erlotinib and 15 mg/kg of bevacizumab every 3 weeks. In the 40 patients enrolled, response rate was 17.5% and median survival was 9.3 months. These results appear promising and have stimulated further studies of this combination in first- and second-line treatment of advanced NSCLC. Selection of Patients for EGFR Inhibitors
Patient characteristics and several molecular markers of the tumor have been described as candidate markers to select patients for treatment with EGFR inhibitors. From multivariate analysis in the randomized trials, particular patient characteristics such as female gender, adenocarcinoma, bronchiolar histology, never-smoking status, and Asian race have been related to drug sensitivity to EGFR inhibitors.[ 24,40] Strikingly, in these patient groups a higher incidence of EGFR mutations in the ATP binding site domain has also been detected, sensitizing for treatment with gefitinib or erlotinib but not for cetuximab. Immunohistochemical staining of the extracellular domain of the EGFR receptor was not correlated with response to gefitinib or erlotinib in NSCLC patients.[22,41,42] Amplification of the EGFR gene detected with FISH and the activity of molecules downstream of EGFR, such as p-Akt, and mutations of K-ras, may play a role in sensitivity to EGFR inhibitors. The presence of K-ras mutations, detected in approximately 30% of NSCLC patients,[ 45] is likely to constitute a useful marker to select those patients that will not benefit from anti-EGFR therapy. However, in a large randomized study of chemotherapy with or without erlotinib as first-line therapy in advanced NSCLC patients, EGFR mutations, detected in 13% of tumors, were associated with longer survival, irrespective of treatment. K-ras mutations, detected in 21% of tumors, were associated with significantly decreased time to progression and survival in patients treated with erlotinib plus chemotherapy.[ 46] These results suggest that EGFR mutations may be a positive prognostic factor for survival that is independent of treatment with erlotinib, and that the combination of EGFR inhibitors and chemotherapy should be avoided in patients with K-ras mutations. Patient characteristics, amplification of the EGFR gene, the presence of EGFR mutations, and the absence of K-ras mutation are all candidates for inclusion in treatment algorithms for individualized treatment with EGFR inhibitors in NSCLC patients. However, the beneficial effects observed in the positive trials cannot be ascribed to the small population of responding patients only. To date, it is too early to exclude patients solely on the basis of one of these characteristics, as none have been validated in prospective clinical trials. Conclusions The introduction of EGFR inhibitors into the treatment of NSCLC is an important development. The side effects are generally less than with chemotherapy. While there is a general effect on symptom control and survival in some studies, limited subgroups of patients particularly benefit from this treatment. The discovery of EGFR mutations in the tyrosine kinase domain may present the possibility of patient selection and novel strategies. Although patient selection based on EGFR mutations only may not be sufficient, this knowledge will stimulate a more rational use of these agents in the future. Also newer drugs with broader activity on multiple pathways are being investigated, which may increase the number of patients who benefit.
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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