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Review Lung Cancer Advancing the Management of Non-small Cell Lung Cancer David F Heigener Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Grosshansdorf, Germany A dvances in the development of targeted therapies and immunotherapy have transformed the management of non small-cell lung cancer (NSCLC). Targeting angiogenesis and molecular drivers of carcinogenesis has led to the approval of several new therapies. More recently, immunotherapeutic approaches have been investigated in the treatment setting of NSCLC. These include immune checkpoint inhibitors (e.g. anti-cytotoxic T-lymphocyte antigen-4 [CTLA-4], anti-programmed death-1 (PD-1) and anti-programmed death- ligand 1 [PD-L1] agents). The emergence of so many therapeutic options offers the potential for personalised therapy. Molecular profiling can inform treatment decisions but there is a need for more data to determine the optimal sequencing and combination of targeted and immunotherapeutic agents. Keywords Non-small cell lung cancer, targeted therapy, checkpoint inhibitors, immunotherapy Disclosure: David F Heigener has participated as a consultant or advisor to Boehringer Ingelheim, Hoffmann-La Roche and Lilly and received honorarium from Lilly, Astra Zeneca, Hoffman-La Roche, Boehringer Ingelheim and Bristol-Myers Squibb. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. Acknowledgements: Medical writing assistance was provided by Kat Mountfort at Touch Medical Media, UK. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. In 2015, more than 430,000 people in the US were living with lung cancer and there were around 221,200 new cases of lung cancer. Deaths from lung cancer are estimated to be in the region of 158,040. 1 Lung cancer is the most frequent cause of cancer deaths in men globally and, in women, lung cancer has surpassed breast cancer as the leading cause of cancer death in developed countries. 2 Data from the National Lung Cancer Audit (LUCADA) for England in 2011 show that the majority of lung cancers (87%) are classified as non-small cell lung cancer (NSCLC). 3 Forty per cent of all NSCLC cases present with stage III cancer and many of them will be considered inoperable. 4 Patients with stage I to IIIa NSCLC are usually treated curatively using surgery, chemotherapy, radiation or a combined modality approach. Patients with advanced disease are generally treated with systematic chemotherapy, although response and survival rates are suboptimal; survival rates for patients diagnosed with stage IIIB and IV NSCLC are just 5% and 1%, respectively. 5,6 Further, only a small proportion of patients benefit from later-line therapies. 7 NSCLC comprises different histological types that are divided into two main groups that inform treatment decision-making: non-squamous carcinoma (including adenocarcinoma, large-cell carcinoma and other cell types) and squamous cell carcinoma. 8 Differences in histological and immunological characteristics of squamous and non-squamous NSCLC are summarised in Table 1. Received: 28 October 2016 Accepted: 6 January 2017 Citation: European Oncology & Haematology, 2017;13(1):53–60 Corresponding Author: David F Heigener, Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Woehrendamm 80, Grosshansdorf 22927, Germany. E: dheigener@aol.com Support: The publication of this article was supported by Lilly. The views and opinions expressed are those of the authors and do not necessarily reflect those of Lilly. The authors provided Lilly with the opportunity to review the article for scientific accuracy before submission. Any resulting changes were made at the author’s discretion. Non-squamous cell NSCLC has benefited from the development of targeted therapies for specific molecular subsets with epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements. Squamous cancers account for between 20% and 30% of NSCLC cases and are still treated with cytotoxic chemotherapy alone. 9–11 Adenocarcinoma, the most common subtype of NSCLC, accounts for approximately 40% of lung cancers in the US, with rising prevalence also seen in Europe. 12,13 Squamous cell carcinoma is closely related to smoking and has a distinct and more complex genetic signature compared with non-squamous tumours. 9 In a National Institutes of Health/AARP cohort of 186,057 women and 266,074 men aged between 50 and 71 years, who were followed for 11 years, relative risks for current smoking and incidence of smoking-related cancers were similar in men and women, probably reflecting converging patterns in smoking. 14 Asthma, chronic obstructive pulmonary disease (COPD) and tuberculosis (TB) were associated with an increased risk of all major subtypes of lung cancer in a Taiwanese population-based study. 15 Women with TB carried the highest risk in this analysis. Advances in the development of targeted therapies and immunotherapy has led to approval by the US Food and Drug Administration (FDA) for 12 agents in the last 10 years (see Table 2). This review aims to review these breakthroughs in the management of NSCLC. Angiogenesis as a target A balance between pro-angiogenic and anti-angiogenic factors regulates angiogenesis in both physiologic and pathologic conditions. 16 In many cancers, including NSCLC, proangiogenic pathways have become established as important and effective therapeutic targets because TOU CH MED ICA L MEDIA 53