Chest
Volume 128, Issue 6, December 2005, Pages 3975-3984
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Reviews
Targeted Therapy for the Treatment of Advanced Non-small Cell Lung Cancer: A Review of the Epidermal Growth Factor Receptor Antagonists

https://doi.org/10.1378/chest.128.6.3975Get rights and content

Lung cancer is the most common cause of cancer death. The vast majority of patients present with non-small cell lung cancer (NSCLC) in advanced inoperable stages. The current first-line treatment for patients with advanced NSCLC includes chemotherapy and palliative radiotherapy, but most patients relapse and eventually succumb to the disease. Advances in our knowledge of cancer cell biology have led to the development of specific molecular-targeted therapeutic agents. Mutations in the epidermal growth factor receptor (EGFR) have been identified in NSCLC cells, and overexpression of the EGFR and its ligands is a common feature of many cancers; therefore, EGFR has become an attractive target for various antitumor strategies. Aberrant signaling from the EGFR is known to be important in the development and progression of NSCLC. Two oral EGFR inhibitors, gefitinib and erlotinib, are small-molecule agents that selectively inhibit the intracellular tyrosine kinase activity of the EGFR. Both have demonstrated antitumor activity in patients with advanced NSCLC who have failed all prior treatment regimens. In addition, the anti-EGFR monoclonal antibody cetuximab has shown promising activity in both first-line and second-line settings in patients with advanced NSCLC. Furthermore, patients with severe comorbidities who would not be eligible for systemic chemotherapy are candidates for these targeted therapies. Finally, these agents have also been shown to be effective for relieving symptoms, maintaining stable disease, and improving quality of life without the adverse events that may be associated with cytotoxic cancer therapies. This report will review the mechanism of action, indications, contraindications, patient selection, and efficacy and side effects of this new class of compounds. It is important for pulmonologists to be aware of this class of compounds, as they can provide benefit to patients with NSCLC who may not have been previously considered for antitumor therapy.

Section snippets

Current Treatment Strategies for the Management of NSCLC

The management of NSCLC largely depends on the stage of disease at diagnosis. The current first-line therapeutic option for patients with advanced NSCLC includes chemotherapy with a platinum (cisplatin or carboplatin) in combination with a third-generation agent (paclitaxel, gemcitabine, vinorelbine, irinotecan) or nonplatinum agents such as docetaxel.5 Docetaxel is considered the standard of care as second-line therapy for those who fail to respond to or are adversely affected by

Epidermal Growth Factor Receptor as a Target for NSCLC

Advances in the understanding of tumor biology have led to the identification of many of the key molecular pathways that drive tumor growth. One such pathway is triggered by activation of the epidermal growth factor receptor (EGFR) [Figure 1].111213 EGFR is a transmembrane glycoprotein belonging to the human EGFR family. It consists of an extracellular ligand-binding domain, a transmembrane region, and a cytoplasmic domain that contains a tyrosine kinase (TK) region.11 TKs are ubiquitously

Novel Agents Target the EGFR

There are two general approaches for inhibiting EGFR signaling: one is to prevent ligand binding to the extracellular domain with a monoclonal antibody, and the other is to inhibit the intracellular TK activity.

EGFR-Targeted Antibodies: Mechanism of Action

The high levels of EGFR expression in NSCLC tumors provide a rationale to investigate EGFR-targeted antibodies. Monoclonal antibodies have been developed to specifically target the extracellular component of the EGFR receptor. They compete with TGF-α, EGF, and other natural ligands for EGFR extracellular binding sites thus preventing autophosphorylation of the intracellular region.18 As a result, the TK domain remains inactive and downstream signaling does not occur, which leads to inhibition

Efficacy of EGFR-Targeted Antibodies in Patients With Advanced NSCLC

Phase I studies of cetuximab demonstrate that this monoclonal antibody has antitumor activity against a variety of solid tumors, including NSCLC, and that it can be safely combined with cisplatin20 and radiotherapy.21 In a recent phase III international trial,21 424 patients with locoregionally advanced squamous cell cancer of the head and neck were randomized to receive either radiation alone (to a dose of 70 Gy) or radiation plus weekly cetuximab (400 mg/m2). The addition of cetuximab to

TK Inhibitors: Mechanism of Action

Inhibitors of TK phosphorylation (TK inhibitors [TKIs]) are small-molecule agents that block EGFR activity by interfering with the adenosine triphosphate-binding site on the intracellular region of the receptor.24 A variety of TKIs have been developed for advanced NSCLC. Gefitinib was the first of the class of EGFR-TKIs to be approved by the FDA for treatment in patients with advanced NSCLC. Gefitinib has been shown to induce radiographic tumor responses, improve symptoms, and improve quality

Gefitinib

Once-daily oral administration of gefitinib has been investigated as monotherapy for advanced, previously treated NSCLC in two non-placebo controlled trials: the first and second IRESSA Dose Evaluation in Advanced Lung Cancer (IDEAL) trials.2526 In the IDEAL trials, patients were randomized to receive either 250 mg/d or 500 mg/d of gefitinib. Patients in IDEAL-1 (n = 210) had previously received one or two chemotherapy regimens; whereas in IDEAL-2, patients (n = 216) had received two or more

Toxicity of Anti-EGFR Therapy

Skin rash is the most common adverse effect associated with anti-EGFR antibodies. Two histologic patterns of rash have been identified: a superficial dermal inflammatory cell infiltrate surrounding hyperkeratotic infundibula, and suppurative, superficial folliculitis.38 Trends toward a dose-dependent incidence of the rash has been reported with anti-EGFR antibodies; however the severity of the rash may not be dose dependent.39 Clinical data suggest a potential relationship between skin rash

Patient Selection

There are several patient populations who should be considered for therapy with the oral targeted agents.5 Currently, the EGFR-TKIs should be considered for patients with advanced or metastatic NSCLC who are refractory to first-line chemotherapy (platinum-based doublet) and second-line chemotherapy (docetaxel or pemetrexed). In addition, these targeted agents offer a new therapy option for patients with advanced NSCLC who have a poor PS, or those who are chemotherapy intolerant. Patients with a

Appropriate Dosing and Length of Treatment

For NSCLC, gefitinib is administered at 250 mg/d, well below the maximum tolerated dose of 700 mg/d. In the IDEAL trials,2526 use of gefitinib at 500 mg/d resulted in higher toxicities with no additional efficacy benefits compared with the 250 mg/d dose. Erlotinib is dosed at 150 mg/d. Trials are currently under way to investigate the use of higher and lower doses of erlotinib in advanced NSCLC.

For all patient subgroups, treatment with EGFR-TKIs should be maintained for as long as the patient

Future Directions

In addition to gefitinib and erlotinib, other EGFR-TKIs are also under investigation in phase I/II trials. Many of these EGFR-TKIs have differing selectivities for the various members of the human EGFR family. CI-1033, a pan-erbB TKI, is a clinically promising agent that is active against all four members of the erbB receptor TK family.50 CI-1033 inhibition is highly selective for erbB1 (EGFR), erbB2, erbB3, and erbB4, and it is currently undergoing phase I clinical trials. As mentioned

Conclusions

Increased knowledge of the mechanistic properties of malignant growth has facilitated the development of molecular-based therapies that can act on specific targets. Anti-EGFR antibodies and EGFR-TKIs have shown efficacy in treating patients with advanced NSCLC who have failed previous first-line and/or second-line cancer therapies. Meaningful benefits for patients with advanced NSCLC include tumor responses, stable disease, and improvements in symptoms and quality of life in about half of the

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