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Review Lung Cancer Immunotherapy and Targeted Therapies in the Treatment of Non-small Cell Lung Cancer Tu Nguyen-Ngoc, 1 Martin Reck, 2 Daniel SW Tan 3 and Solange Peters 1 1. Department of Medical Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland; 2. Department of Thoracic Oncology, Lungen Clinic, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 3. Division of Medical Oncology, National Cancer Centre Singapore, Singapore I n the last decade, the emergence of targeted therapies has changed the treatment paradigm for non-small cell lung cancer (NSCLC). The growing availability of therapies targeting specific genetic alterations, such as epidermal growth factor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements, have led to changes in the guidelines to reflect the need for molecular profiling. More recently, immunotherapeutic approaches have been investigated in the treatment setting of NSCLC, and these may provide superior outcomes and have substantially better tolerability compared to chemotherapy. Immunotherapies currently available for NSCLC include the checkpoint inhibitors anti-PD-1 antibodies nivolumab and pembrolizumab. Several other anti-PD-L1 compounds such as atezolizumab, durvalumab and avelumab are also very advanced in clinical investigation, in monotherapy as well as in combination with immune priming phase activators anti-CTLA4 ipilimumab and tremelimumab, across all treatment lines. The challenge facing oncologists is identifying which therapy is best suited to the individual patient. Keywords Non-small cell lung cancer, targeted therapy, checkpoint inhibitors, immunotherapy Disclosure: Tu Nguyen-Ngoc is supported by the Leenaards Foundation. Martin Reck has received personal honoraria for lectures and consultancy from F. Hoffmann-La Roche, Lilly, BMS, MSD, AstraZeneca, Merck, Boehringer-Ingelheim, Pfizer, Novartis and Celgene. Daniel SW Tan has been an advisor and consultant to Novartis, Bayer, Boehringer-Ingelheim, Merrimack and Pfizer, received travel funding and honorarium from Merck, Pfizer, Novartis, AstraZeneca, Boehringer- Ingelheim and Ariad, and received research funding from Novartis, GSK, Bayer and AstraZeneca. Solange Peters has provided consultation, attended advisory boards and/or provided lectures for F. Hoffmann–La Roche, Eli Lilly and Company Oncology, AstraZeneca, Pfizer, Boehringer-Ingelheim, BMS, Daiichi-Sankyo, Morphotek, Merrimack, Merck Serono, Amgen, Clovis and Tesaro, for which she received honoraria. 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. Acknowledgments: 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. Received: 5 September 2016 Accepted: 19 November 2016 Citation: European Oncology & Haematology, 2017;13(1):35–52 Corresponding Author: Solange Peters, Department of Medical Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland. E: Support: The publication of this article was supported by Novartis. The views and opinions expressed are those of the authors and do not necessarily reflect those of Novartis. The authors provided Novartis with the opportunity to review the article for scientific accuracy before submission. Any resulting changes were made at the author’s discretion. TOU CH MED ICA L MEDIA Lung cancer is the leading cause of cancer mortality worldwide 1 and remains one of the major therapeutic challenges in oncology. Traditionally, lung cancer is subdivided based on histology: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) have completely different molecular and therapeutic profiles. The most common class is NSCLC, accounting for 85% of all cases. 2 The prognosis of NSCLC dramatically changed following the discovery of genetic alterations affecting oncogenes, called drivers, including epidermal growth factor (EGFR) mutations, anaplastic lymphoma kinase (ALK) rearrangement, ROS1 or RET rearrangements, MET mutations or amplification, as well as BRAF or HER2 mutations (see Figure 1). The ability to target tumours at the molecular level has led to a paradigm shift in the management of patients with these mutations. The availability of new therapies with differing modes of action is potentially confusing, not only for primary care physicians but also for medical oncologists. Furthermore, unmet needs remain in the treatment of NSCLC, including the development of resistance to targeted therapies and the fact that not all molecular subtypes are actionable to date. Furthermore, a large group of patients does not suffer from tumours characterised by oncogenic alterations, with the vast majority deprived of any actionable genetic change. These patients are currently treated by chemotherapy. There is a need for new treatments for these patients, and immunotherapy represents a promising approach, but also confers a challenge: identifying patients who will benefit optimally from these treatments. This article aims to discuss the use of targeted therapies and immunotherapy in the setting of NSCLC. Targeted therapies for non-small cell lung cancer Standard-of-care molecular characterisation of advanced NSCLC is performed by analysis of activating mutations of EGFR (in exons 19 and 21) and detection of an ALK rearrangement. 3 Such screening of NSCLC patients for driver mutations have been standardised and validated. 4 However, mutations on the EGFR gene are seen in fewer than 10% of NSCLC patients in Western populations, 5,6 although this is higher (up to 50%) in Asian populations. 5,7 The mutation has been reported with a higher frequency in non-smokers, women, and presence of adenocarcinoma. 6 Clinical trials of approved targeted therapies for NSCLC are summarised in Table 1. The use of EGFR tyrosine kinase inhibitors (TKIs) is recommended as first-line therapy 35