Elsevier

Lung Cancer

Volume 67, Issue 3, March 2010, Pages 257-274
Lung Cancer

Review
Targeted therapies for non-small cell lung cancer

https://doi.org/10.1016/j.lungcan.2009.10.012Get rights and content

Abstract

Non-small cell lung cancer (NSCLC) accounts for approximately 80–85% of all cases of lung cancer, and it is the most common cause of death in men and second only to breast cancer in women. Combination chemotherapy, usually platinum-based, is currently the first-line therapy of choice, however, the prognosis for patients with advanced NSCLC remains poor with a median survival time of 8–11 months and a 1-year survival rate of 30%. The treatment of NSCLC is therefore a major unmet need and new therapies focusing on the molecular mechanisms that mediate growth of NSCLC cells are urgently needed. The availability of agents targeted against the EGF-R, as well as the anti-VEGF agent bevacizumab, have provided some clinical benefit. Numerous other novel targeted therapies are now in clinical development and may have potential for overcoming the limitations associated with currently available drugs. In addition, a few new agents targeting novel pathways are also under clinical evaluation. 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 this article we review clinical data for molecular-targeted therapies in NSCLC, with emphasis on EGF-R, VEGF-R and other novel targets. Nonetheless, for most patients with NSCLC targeted therapies have not dramatically changed clinical outcome, and resistance has emerged as a clinical problem. The molecular complexity of lung cancer underlies these disappointments and stresses the need for optimizing treatment by seeking a more personalized approach to care. Therefore, clinical trials that investigate the activity of novel agents, and incorporate patient selection based on clinical and molecular factors, are required. The increased sophistication of preclinical models and the enrollment of patients in clinical trials that include measurements of biomarkers will clearly help to identify patients who are likely to benefit from therapy, as well as further define mechanisms of resistance to therapy.

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.

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      Citation Excerpt :

      Lung cancer represents the most frequently diagnosed solid malignancy and the leading cause of cancer-related death worldwide, for which harbors both the highest incidence and mortality in both men and women worldwide [1]. Non-small cell lung cancer (NSCLC) is the main subset of lung cancer, and it approximately accounts for 80–85% of the disease [2]. Although the application of low-dose spiral computed tomography detects the disease at an early stage, approximately 50% of the patients are still diagnosed with locally advanced or metastatic disease [3].

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