The National Lung Matrix Trial : translating the biology of stratification in advanced non-small-cell lung cancer

Research output: Contribution to journalArticle

Authors

  • L R Crack
  • S Popat
  • C Swanton
  • S J Hollingsworth
  • R Buller
  • I Walker
  • T H Carr
  • D Wherton

External organisations

  • Department of Medicine, Royal Marsden NHS Foundation Trust, London
  • The Francis Crick Institute, London
  • UCL Cancer Institute, CRUK Lung Cancer Centre of Excellence, London
  • Innovative Medicines Oncology, AstraZeneca, Cambridge
  • Pfizer Oncology, Pfizer, San Diego
  • Strategy and Research Funding, Cancer Research UK, London

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.

PATIENTS AND 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.

CONCLUSION: 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.

CLINICAL TRIAL ISRCTN: 38344105.

Bibliographic note

© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Details

Original languageEnglish
Pages (from-to)2464-2469
JournalAnnals of Oncology
Volume26
Issue number12
Early online date25 Sep 2015
Publication statusPublished - 12 Dec 2015

Keywords

  • National Lung Matrix Trial, non-small-cell lung cancer, stratified medicine, adaptive trial design, Umbrella Trial