ReviewTargeted therapies for non-small cell lung cancer
Introduction
Non-small cell lung cancer (NSCLC) accounts for approximately 80–85% of all cases of lung cancer, and is the most common cause of death in men and second only to breast cancer in woman [1]. Treatment of NSCLC is guided by disease stage. Surgery is the treatment of choice for early-stage localized disease, whereas multimodality therapy remains the norm for patients with locally advanced disease. Patients with advanced metastatic disease may derive a benefit from palliative chemotherapy. About 40% of patients with NSCLC present at an advanced stage, with metastatic or locally advanced disease, which underscores the importance of identifying therapeutic schemes that may benefit this large patient population. Combination chemotherapy, usually platinum-based, is currently the first-line therapy of choice [2]. Based on various studies, doublet regimens containing cisplatin or carboplatin with paclitaxel, gemcitabine, docetaxel, vinorelbine or irinotectan are administered [3]. The choice of combination drugs, however, varies in different countries, but several studies have shown similar degrees of efficacy among different combinations in the treatment of advanced NSCLC [4]. According to the ASCO guidelines [3] first-line chemotherapy should be stopped at 4 cycles in patients who are not responding and administered for no more than 6 cycles. Data from a recently published meta-analysis suggest that extending chemotherapy (>6 cycles), particularly with a third-generation regimen, improved progression-free survival (PFS) substantially, but had only modest effects on overall survival (OS) [5].
The prognosis for patients with advanced NSCLC is poor. Recent, large, randomized phase III trials have demonstrated that platinum-based chemotherapy combinations yield a median survival time of 8–11 months, a 1-year survival rate of 30–45% and a 2-year survival rate of 10–20% [6], [7]. A landmark meta-analysis has shown that the use of chemotherapy in patients with advanced NSCLC, when compared with best supportive care (BSC), produced an improvement of 10% in 1-year survival and 2 months in median survival [8]. Although these results were statistically significant, the magnitude of this benefit is modest, and the duration of chemotherapy that maximizes survival benefit and symptom palliation in advanced NSCLC is currently unclear. The treatment of NSCLC is therefore a major unmet need and new therapies focusing on the molecular mechanisms that mediate the growth of lung cancer cells are urgently needed.
Section snippets
Cetuximab
Monoclonal antibodies that bind the extracellular domain of EGF-R prevent the receptor from interacting with its ligand, EGF, and thus prevent intracellular signal transduction. In addition, antibodies have the inherent ability to recruit effector cells such as macrophages and monocytes to the tumor through the binding of the antibody constant Fc domain to specific receptors on these cells [9]. Cetuximab (Erbitux®, Merck, Germany) is a chimeric monoclonal antibody (IgG1 subtype) that
EGF-R inhibitors
The discovery of somatic mutations in the tyrosine kinase domain of EGF-R in NSCLC represents a dramatic step in elucidating genomic changes in lung cancer and their role in developing treatment strategies. These gain-of-function mutations enhance EGF-R activation, markedly increase sensitivity to EGF-R RTK inhibitors and are transforming. Retrospective studies suggest particularly promising results with EGF-R RTK inhibitors therapy among patients harboring EGF-R mutations, with response rates
mTOR inhibitors
The mammalian target of rapamycin (mTOR) is a serine-threonine kinase that functions as a central regulator of multiple signalling pathways that control cell growth, division, metabolism, and angiogenesis [106], [107]. Clinical trials are ongoing with rapamycin and its analogs temsirolimus (torisel, Pfizer, formerly Wyeth, USA), everolimus (RAD001, Novartis, Switzerland) and deforolimus (Ariad Pharmaceuticals, USA) in various tumor types. Although mTOR plays a central role in many biologic
Conclusion
Despite recent advances in NSCLC treatment clinical outcome of these patients still remains a challenge. The search for innovative therapeutic agents in NSCLC that are more effective and have fewer side effects than older chemotherapeutic drugs has spurred the development of more than 500 molecularly targeted agents and thereby has introduced the concept of individualized therapy. In the process of identifying targets for therapy, our understanding of the molecular pathways involved in
Conflict of interest statement
Professor Wolfram C. M. Dempke: None declared. Dr. Tamas Suto: Employee of Amgen. Dr. Martin Reck: None declared.
Acknowledgements
We thank Dr. Silke Zaun (AstraZeneca Pharmaceuticals) and Dr. Barbara Bornkessel for editorial assistance provided. The authors are indebted to Alwin Hierl (Munich) for his help with the art work.
References (150)
- et al.
Multicentre randomized phase III study comparing the same dose and schedule of cisplatin plus the same schedule of vinorelbine or gemcitabine in advanced non-small cell lung cancer
Eur J Cancer
(2005) - et al.
Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer
Ann Oncol
(2008) - et al.
Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomized phase III trial
Lancet
(2009) - et al.
Subgroup results from a randomised, double-blind, multicentre phase III study of bevacizumab in combination with cisplatin-gemcitabine in chemotherapy-naïve patients with advanced or recurrent non-squamous nonsmall cell lung cancer (NSCLC): study BO17704
Eur J Cancer
(2007) - et al.
Resistance to EGF-R (erbB-1) and VEGF-R modulating agents
Eur J Cancer
(2009) - et al.
The prognostic significance of pretreatment plasma levels of insulin-like growth factor (IGF)-1, IGF-2, and IGF binding protein-3 in patients with advanced non-small cell lung cancer
Lung Cancer
(2006) Quantitative gene expression in non-small cell lung cancer from paraffin-embedded tissue specimen: predicting response to gefitinib, an EGFR kinase inhibitor
Lung Cancer
(2003)- et al.
Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survial Evaluation in Lung Cancer)
Lancet
(2005) - et al.
Gefitinib (IRESSA) in patients of Asian origin with refractory advanced non-small cell lung cancer: subset analysis from the ISEL trial
J Thorac Oncol
(2006) - et al.
Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial
Lancet
(2008)
Met pathway as a therapeutic target
J Thorac Oncol
Molecular mechanisms of lymphangiogenesis in health and disease
Cancer Cell
Targeted therapy against VEGFR and EGFR with ZD6474 enhances the therapeutic efficacy of irradiation in an orthotopic model of human non-small-cell lung cancer
Int J Radiat Oncol Biol Phys
A phase II study of continuous daily sunitinib dosing in patients with previously-treated advanced non-small cell lung cancer (NSCLC)
J Thorac Oncol
Systemic chemotherapy for advanced non-small cell lung cancer: recent advances and future directions
Oncologist
Second-line chemotherapy for non-small cell lung cancer
Expert Rev Anticancer Ther
American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003
J Clin Oncol
Comparison of four chemotherapy regimes for advanced non-small cell lung cancer
N Engl J Med
Duration of chemotherapy for advanced non-small-cell lung cancer: a systematic review and meta-analysis of randomized trials
J Clin Oncol
Gemcitabine plus carboplatin versus mitomycin, ifosfamide, and cisplatin in patients with stage IIIB or IV non small cell lung cancer. A phase III randomized study of the London Cancer Group
J Clin Oncol
Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials
BMJ
Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets
Nat Med
Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer
N Engl J Med
Cetuximab and other anti-epidermal growth factor receptor monoclonal antibodies in the treatment of non-small cell lung cancer
Oncologist
A randomized multicenter phase III study of cetuximab (Erbitux®) in combination with taxane/carboplatin versus taxane/carboplatin alone as first-line treatment for patients with advanced/metastatic non-small cell lung cancer (NSCLC)
J Thorac Oncol
Summary statement novel agents in the treatment of lung cancer
J Thorac Oncol
Recent advances of novel targeted therapy in non-small cell lung cancer
J Hema Oncol
Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer
J Clin Oncol
Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer
N Engl J Med
Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAiL
J Clin Oncol
ECOG 4599 phase III trial of carboplatin and paclitaxel ± bevacizumab: subset analysis of survival by gender
J Clin Oncol
Outcomes for elderly, advanced-stage non-small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group trial 4599
J Clin Oncol
MO19390 (SAiL): safety and efficacy of first-line bevacizumab (BV)-based therapy in advanced non-small cell lung cancer (NSCLC)
J Clin Oncol
Preliminary safety and effectiveness of bevacizumab (BV) based treatment in subpopulations of patients (pts) with non-small cell lung cancer (NSCLC) from the ARIES study: a bevacizumab (BV) treatment observational cohort study (OCS)
J Clin Oncol
Acceptable safety of bevacizumab therapy in patients with brain metastases due to non-small cell lung cancer
J Clin Oncol
A randomized, double-blind, placebo-controlled, phase IIIb trial (ATLAS) comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC)
J Clin Oncol
A phase III multicenter, placebo-controlled, double-blind, randomized clinical trial to evaluate the efficacy of bevacizumab (Avastin®) in combination with erlotinib (Tarceva®) compared with erlotinib alone for treatment of advanced non-small cell lung cancer after failure of standard first-line chemotherapy (BETA)
J Thorac Oncol
Acquired resistance to EGFR-tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins
J Clin Invest
Insulin-like growth factor 1 receptor targeted therapeutics: novel compounds and novel treatment strategies for cancer medicine
Recent Pat Anticancer Drug Discov
Phase I dose escalation trial of the anti insulin-like growth factor-I receptor monoclonal antibody CP-751,871 in patients with refractory solid tumors
Clin Cancer Res
Phase I, pharmacokinetic and pharmacodynamic study of the anti-insulin like growth factor type 1 receptor monoclonal antibody CP-751,871 in patients with multiple myeloma
J Clin Oncol
Phase II study of the anti-insulin-like growth factor type 1 receptor antibody CP-751,871 in combination with paclitaxel and carboplatin in previously untreated, locally advanced, or metastatic non-small-cell lung cancer
J Clin Oncol
First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations
J Clin Oncol
Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinoma with acquired resistance to kinase inhibitors
Clin Cancer Res
Mutations in the epidermal growth factor receptor gene and effects of EGFR-tyrosine kinase inhibitors on lung cancer
Gen Thorac Cardiovasc Surg
Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib
Clin Cancer Res
Multi-Institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer
J Clin Oncol
Getting the grips with gefitinib
Lancet Oncol
EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy
Science
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