Chest
ReviewsTargeted Therapy for the Treatment of Advanced Non-small Cell Lung Cancer: A Review of the Epidermal Growth Factor Receptor Antagonists
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
References (53)
Targeting HER1/EGFR: a molecular approach to cancer therapy
Semin Oncol
(2003)- et al.
Epidermal growth factor-related peptides and their receptors in human malignancies
Crit Rev Oncol Hematol
(1995) - et al.
What is a clinically meaningful change on the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire? Results from Eastern Cooperative Oncology Group (ECOG) Study 5592
J Clin Epidemiol
(2002) - et al.
Final results from a phase II study of erlotinib (TarcevaTM) monotherapy in patients with advanced non-small cell lung cancer following failure of platinum-based chemotherapy
Lung Cancer
(2003) - et al.
Dermatologic side effects associated with gefitinib therapy: clinical experience and management
Clin Lung Cancer
(2003) - et al.
Severe acute interstitial pneumonia and gefitinib
Lancet
(2003) - et al.
CI-1033, a pan-erbB tyrosine kinase inhibitor
Semin Oncol
(2001) - et al.
Beliefs among pulmonologists and thoracic surgeons in the therapeutic approach to non-small cell lung cancer
Chest
(2000) Cancer Facts & Figures 2004
(2004)- et al.
Cancer statistics 2000
CA Cancer J Clin
(2000)
Cancer statistics 2003
CA Cancer J Clin
Cancer statistics 1999
CA Cancer J Clin
American Society of Clinical Oncology treatment of unresectable non-small cell lung cancer guideline: update 2003
J Clin Oncol
Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy
J Clin Oncol
Second line chemotherapy for NSCLC: establishing a gold standard
Lung Cancer
Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer
N Engl J Med
Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials
BMJ
Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small cell lung cancer previously treated with chemotherapy
J Clin Oncol
Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy
Drugs
The relationship of quantitative epidermal growth factor receptor expression in non-small cell lung cancer to long term survival
Br J Cancer
Expression of epidermal growth factor receptor (EGF-R) in human lung tumors
Br J Cancer
Immunohistochemical evidence of autocrine growth factors in adenocarcinoma of the human lung
Cancer Res
Overexpression of the epidermal growth factor receptor and its ligand transforming growth factor α is frequent in resectable non-small cell lung cancer but does not predict tumor progression
Clin Cancer Res
New technologies in epidermal growth factor receptor-targeted cancer therapy: an overview of novel therapeutic agents in development
Signal
IMC-C225: an anti-epidermal growth factor receptor monoclonal antibody for the treatment of head and neck cancers
Expert Opin Biol Ther
Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin
J Clin Oncol
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Effect of gefitinib plus Chinese herbal medicine (CHM) in patients with advanced non-small-cell lung cancer: A retrospective case-control study
2014, Complementary Therapies in MedicineCitation Excerpt :The incidence of rash in GF group was statistically lower than that in G group (P = 0.048). Gefitinib, as a member of the “small molecule” tyrosine kinase inhibitors (TKI),16,17 is a standard first-line treatment for NSCLC patients with EGFR mutation. Several randomized phase III trials demonstrated that gefitinib prolonged progression-free survival and improved quality of life compared with platinum-based doublet chemotherapy.4–6
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