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Editorial Lung Cancer The Two Revolutions in the Treatment of Advanced Non-small Cell Lung Cancer Maurice Pérol Department of Medical Oncology, Léon Bérard Cancer Center, Lyon, France Abstract In parallel with the evolution of therapeutic paradigms for advanced cancers, treatment of advanced non-small cell lung cancer (NSCLC) has been through the revolution of personalised medicine benefiting for a minority of patients whose disease depends on a single oncogenic genetic alteration targetable by specific tyrosine kinase inhibitors. As well as for some other tumour types, targeting immune checkpoints inhibitors has shown encouraging activity for some patients, suggesting the dawn of a second therapeutic revolution for a significant proportion of lung cancer patients. Keywords Non-small cell lung cancer, chemotherapy, targeted therapy, immunotherapy Disclosure: Maurice Pérol has received honoraria for advisory boards from Eli Lilly, Roche, Genentech, Boehringer-Ingelheim, Astra-Zeneca, Novartis, Pfizer, Clovis, Pierre Fabre and Merck. No funding was received in the publication of this article. This article is a short opinion piece and has not been submitted to external peer reviewers. 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: 18 March 2016 Published Online: 24 May 2016 Citation: European Oncology & Haematology, 2016;12(1):15–6 Correspondence: Maurice Pérol, Department of Medical Oncology, Léon Bérard Cancer Center, 28 Rue Laënnec, 69008 Lyon, France. Changes that have been occurring since approximately 10 years in the treatment of advanced non-small cell lung cancer (NSCLC) constitute a good illustration of the evolving paradigms in oncology. Ten years ago, advanced NSCLC was considered as a single entity, resulting from tumour cells proliferation and was therefore treated with cytotoxic drugs. With this approach, it has been possible to obtain a small but significant prolongation of survival in first-line of treatment with platinum-based chemotherapy, 1 in second-line with docetaxel, 2 both compared to best supportive care and in second or third-line therapy with erlotinib in unselected patients compared to placebo. 3 Even if it was possible to give several successive lines of treatment including now maintenance chemotherapy in a significant proportion of NSCLC patients, improvement of survival was limited and median survival consistently remained below one year. 4 Clearly, other approaches seemed necessary to cross this one-year bar for median survival, all the more since this survival advantage might be also linked to stage migration due to improvement in staging techniques, increase in patients’ selection for clinical trials and optimisation of supportive care. 5 demonstration that lung adenocarcinoma could result from one single genetic alteration, leading to an “oncogenic addiction” for tumour cells, which proliferation and survival depend on this genetically altered pathway. The Iressa Pan-Asia Study (IPASS) trial comparing gefitinib to chemotherapy in never-smoker Asian patients 9 was therefore a landmark trial showing that genetic criteria were superior to clinical characteristics for selecting the adequate treatment for these patients and that gefitinib provided a progression-free survival advantage over chemotherapy only in patients with EGFR activating mutations. Moreover, the improvement of survival for patients with EGFR mutations treated with EGFR tyrosine kinase inhibitors with a median survival of more than 30 months in some trials, indirectly proves that targeting the oncogenic signalling pathway undeniably changes the natural history of the disease. 10 Besides EGFR mutations, other oncogenic single genetic alterations have been identified, the first of which being the anaplastic lymphoma kinase (ALK) gene rearrangements that led to a rapid development of crizotinib as ALK inhibitor with a clear improvement of patients survival. 11 It is now possible to individualise some oncogenic A first step for treatment personalisation came from taking histology into consideration for first and second-line treatment of advanced NSCLC. This resulted from the development of two drugs, first pemetrexed demonstrating activity only in non-squamous carcinoma 6 and second, bevacizumab with the evidence of crippling toxicity in squamous cell carcinoma. 7 However, the true first revolution was due to the discovery of mutations in the gene encoding for epidermal growth factor receptor (EGFR), even there in relation to a drug development by sequencing EGFR in patients responding to gefitinib. 8 This was the first genetic alterations in non-squamous carcinoma (EGFR, v-Raf murine sarcoma viral oncogene homolog B [BRAF], human epidermal growth factor receptor-2 [HER2], mesenchymal-epithelial transition [MET] or V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog [KRAS] mutations, ALK, c-ros oncogene 1 [ROS1], rearranged during transfection [RET], neurotrophic tyrosine receptor kinase [NTRK] rearrangements) with available corresponding specific targeted therapies (except for KRAS mutations) able to provide good and durable response. 12 Therefore, NSCLC should be considered as a group of distinct diseases on the basis of genome analysis rather as a single entity. 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