title: The National Lung Matrix Trial: translating the biology of stratification in advanced non-small-cell lung cancer.
abstract: BACKGROUND
  The management of NSCLC has been transformed by stratified medicine. The National Lung Matrix Trial (NLMT) is a UK-wide study exploring the activity of rationally selected biomarker/targeted therapy combinations.
  
  
  METHODS
  The Cancer Research UK (CRUK) Stratified Medicine Programme 2 is undertaking the large volume national molecular pre-screening which integrates with the NLMT. At study initiation, there are eight drugs being used to target 18 molecular cohorts. The aim is to determine whether there is sufficient signal of activity in any drug-biomarker combination to warrant further investigation. A Bayesian adaptive design that gives a more realistic approach to decision making and flexibility to make conclusions without fixing the sample size was chosen. The screening platform is an adaptable 28-gene Nextera next-generation sequencing platform designed by Illumina, covering the range of molecular abnormalities being targeted. The adaptive design allows new biomarker-drug combination cohorts to be incorporated by substantial amendment. The pre-clinical justification for each biomarker-drug combination has been rigorously assessed creating molecular exclusion rules and a trumping strategy in patients harbouring concomitant actionable genetic abnormalities. Discrete routes of pathway activation or inactivation determined by cancer genome aberrations are treated as separate cohorts. Key translational analyses include the deep genomic analysis of pre- and post-treatment biopsies, the establishment of patient-derived xenograft models and longitudinal ctDNA collection, in order to define predictive biomarkers, mechanisms of resistance and early markers of response and relapse.
  
  
  CONCLUSIONS
  The SMP2 platform will provide large scale genetic screening to inform entry into the NLMT, a trial explicitly aimed at discovering novel actionable cohorts in NSCLC.
  38344105.
authors.affiliation: Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham Department of Oncology, University Hospitals Birmingham NHS Foundation Trust, Birmingham g.middleton@bham.ac.uk.
authors.forename: G
authors.initials: G
authors.lastname: Middleton
authors.affiliation: Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham.
authors.forename: L R
authors.initials: LR
authors.lastname: Crack
authors.affiliation: Department of Medicine, Royal Marsden NHS Foundation Trust, London.
authors.forename: S
authors.initials: S
authors.lastname: Popat
authors.affiliation: The Francis Crick Institute, London UCL Cancer Institute, CRUK Lung Cancer Centre of Excellence, London.
authors.forename: C
authors.initials: C
authors.lastname: Swanton
authors.affiliation: Innovative Medicines Oncology, AstraZeneca, Cambridge, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Hollingsworth
authors.affiliation: Pfizer Oncology, Pfizer, San Diego, USA.
authors.forename: R
authors.initials: R
authors.lastname: Buller
authors.affiliation: Strategy and Research Funding, Cancer Research UK, London, UK.
authors.forename: I
authors.initials: I
authors.lastname: Walker
authors.affiliation: Innovative Medicines Oncology, AstraZeneca, Cambridge, UK.
authors.forename: T H
authors.initials: TH
authors.lastname: Carr
authors.affiliation: Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham.
authors.forename: D
authors.initials: D
authors.lastname: Wherton
authors.affiliation: Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham.
authors.forename: L J
authors.initials: LJ
authors.lastname: Billingham
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D057170:Translational Research, Biomedical / Q000379:methods* / Q000639:trends; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D011743:Pyrimidines; D011758:Pyrroles; D051057:Proto-Oncogene Proteins c-akt; C575618:capivasertib
keywords: National Lung Matrix Trial; Umbrella Trial; adaptive trial design; non-small-cell lung cancer; stratified medicine