Landmark Studies of Targeted Therapies for Advanced Non-Small Cell Lung Cancer: A Guide for Pulmonologists

Author(s): Adrien Costantini, Theodoros Katsikas, Clementine Bostantzoglou*

Journal Name: Current Respiratory Medicine Reviews

Volume 16 , Issue 1 , 2020

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Over the past decade, major breakthroughs in the understanding of lung cancer histology and mutational pathways have radically changed diagnosis and management. More specifically, in non-small cell lung cancer (NSCLC), tumour characterisation has shifted from differentiating based solely on histology to characterisation that includes genetic profiling and mutational status of Epidermal Growth Factor (EGFR), Anaplastic Lymphoma Kinase (ALK), c-ros oncogene 1 (ROS1) and BRAF. These genetic alterations can be targeted by specific drugs that result in improved progression-free survival, as well as higher response rates and are currently standard of care for NSCLC patients harbouring these mutations. In this a narrative, non-systematic review we aim to handpick through the extensive literature and critically present the ground-breaking studies that lead to the institution of tailored treatment options as the standard of care for the main targetable genetic alterations.

Keywords: Anaplastic lymphoma kinase, epidermal growth factor, non-small-cell lung cancer, targeted therapies, tyrosine kinase inhibitors, mutation.

Cancer WHO; [accessed: November 1, 2018] Available from:
Barlesi F, Mazieres J, Merlio J-P, et al. Biomarkers France contributors. Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT). Lancet 2016; 387(10026): 1415-26.
[] [PMID: 26777916]
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353(2): 123-32.
[] [PMID: 16014882]
Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 2008; 372(9652): 1809-18.
[] [PMID: 19027483]
Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350(21): 2129-39.
[] [PMID: 15118073]
Mok TS, Wu Y-L, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361(10): 947-57.
[] [PMID: 19692680]
Maemondo M, Inoue A, Kobayashi K, et al. North-East Japan Study Group. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010; 362(25): 2380-8.
[] [PMID: 20573926]
Rosell R, Carcereny E, Gervais R, et al. Spanish Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012; 13(3): 239-46.
[] [PMID: 22285168]
Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011; 12(8): 735-42.
[] [PMID: 21783417]
Mitsudomi T, Morita S, Yatabe Y, et al. West Japan Oncology Group. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010; 11(2): 121-8.
[] [PMID: 20022809]
Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31(27): 3327-34.
[] [PMID: 23816960]
Wu Y-L, Zhou C, Hu C-P, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol 2014; 15(2): 213-22.
[] [PMID: 24439929]
Mok TS, Wu Y-L, Ahn M-J, et al. AURA3 Investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med 2017; 376(7): 629-40.
[] [PMID: 27959700]
Soria J-C, Ohe Y, Vansteenkiste J, et al. FLAURA investigators. osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018; 378(2): 113-25.
[] [PMID: 29151359]
Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007; 448(7153): 561-6.
[] [PMID: 17625570]
Kwak EL, Bang Y-J, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010; 363(18): 1693-703.
[] [PMID: 20979469]
Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013; 368(25): 2385-94.
[] [PMID: 23724913]
Solomon BJ, Mok T, Kim DW, et al. PROFILE 1014 Investigators. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014; 371(23): 2167-77.
[] [PMID: 25470694]
Peters S, Camidge DR, Shaw AT, et al. ALEX Trial Investigators. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med 2017; 377(9): 829-38.
[] [PMID: 28586279]
Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in multiple nonmelanoma cancers with BRAFV600 mutations. N Engl J Med 2015; 373(8): 726-36.
[] [PMID: 26287849]
Planchard D, Smit EF, Groen HJM, et al. Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol 2017; 18(10): 1307-16.
[] [PMID: 28919011]
Bergethon K, Shaw AT, Ou S-HI, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012; 30(8): 863-70.
[] [PMID: 22215748]
Acquaviva J, Wong R, Charest A. The multifaceted roles of the receptor tyrosine kinase ROS in development and cancer. Biochim Biophys Acta 2009; 1795(1): 37-52.
[PMID: 18778756]
Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 2014; 371(21): 1963-71.
[] [PMID: 25264305]

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Article Details

Year: 2020
Published on: 15 September, 2020
Page: [5 - 10]
Pages: 6
DOI: 10.2174/1573398X16666200319134739
Price: $65

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