title: Advances in the Development of Molecularly Targeted Agents in Non-Small-Cell Lung Cancer.
abstract: Non-small-cell lung cancer (NSCLC) remains a significant global health challenge and the leading cause of cancer-related mortality. The traditional 'one-size-fits-all' treatment approach has now evolved into one that involves personalized strategies based on histological and molecular subtypes. The molecular era has revolutionized the treatment of patients harboring epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and ROS1 gene aberrations. In the appropriately selected population, anti-tumor agents against these molecular targets can significantly improve progression-free survival. However, the emergence of acquired resistance is inevitable. Novel potent compounds with much improved and rational selectivity profiles, such as third-generation EGFR T790M resistance mutation-specific inhibitors, have been developed and added to the NSCLC armamentarium. To date, attempts to overcome resistance bypass pathways through downstream signaling blockade has had limited success. Furthermore, the majority of patients still do not harbor known driver genetic or epigenetic alterations and/or have no new available treatment options, with chemotherapy remaining their standard of care. Several potentially actionable driver aberrations have recently been identified, with the early clinical development of multiple inhibitors against these promising targets currently in progress. The advent of immune checkpoint inhibitors has led to significant benefit for advanced NSCLC patients with durable responses observed. Further interrogation of the underlying biology of NSCLC, coupled with modern clinical trial designs, is now required to develop novel targeted therapeutics rationally matched with predictive biomarkers of response, so as to further advance NSCLC therapeutics through the next decade.
authors.affiliation: Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: Saoirse O
authors.initials: SO
authors.lastname: Dolly
authors.affiliation: Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: Dearbhaile C
authors.initials: DC
authors.lastname: Collins
authors.affiliation: Royal Marsden NHS Foundation Trust, London, UK.|National University Health System, Singapore, Singapore.
authors.forename: Raghav
authors.initials: R
authors.lastname: Sundar
authors.affiliation: Royal Marsden NHS Foundation Trust, London, UK.|National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Popat
authors.affiliation: Royal Marsden NHS Foundation Trust, London, UK. timothy.yap@icr.ac.uk.|Drug Development Unit and Lung Cancer Unit, The Institute of Cancer Research and Royal Marsden Hospital, Downs Road, London, SM2 5PT, UK. timothy.yap@icr.ac.uk.
authors.forename: Timothy A
authors.identifier: http://orcid.org/0000-0002-7140-4534
authors.initials: TA
authors.lastname: Yap
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D058990:Molecular Targeted Therapy
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor