The National Lung Matrix Trial of personalized therapy in lung cancer.

Abstract

The majority of targeted therapies for non-small-cell lung cancer (NSCLC) are directed against oncogenic drivers that are more prevalent in patients with light exposure to tobacco smoke1-3. As this group represents around 20% of all patients with lung cancer, the discovery of stratified medicine options for tobacco-associated NSCLC is a high priority. Umbrella trials seek to streamline the investigation of genotype-based treatments by screening tumours for multiple genomic alterations and triaging patients to one of several genotype-matched therapeutic agents. Here we report the current outcomes of 19 drug-biomarker cohorts from the ongoing National Lung Matrix Trial, the largest umbrella trial in NSCLC. We use next-generation sequencing to match patients to appropriate targeted therapies on the basis of their tumour genotype. The Bayesian trial design enables outcome data from open cohorts that are still recruiting to be reported alongside data from closed cohorts. Of the 5,467 patients that were screened, 2,007 were molecularly eligible for entry into the trial, and 302 entered the trial to receive genotype-matched therapy-including 14 that re-registered to the trial for a sequential trial drug. Despite pre-clinical data supporting the drug-biomarker combinations, current evidence shows that a limited number of combinations demonstrate clinically relevant benefits, which remain concentrated in patients with lung cancers that are associated with minimal exposure to tobacco smoke.

• Authors: Gary Middleton, Peter Fletcher, Sanjay Popat, Joshua Savage, Yvonne Summers, Alastair Greystoke, David Gilligan, Judith Cave, Noelle O'Rourke, Alison Brewster, Elizabeth Toy, James Spicer, Pooja Jain, Adam Dangoor, Melanie Mackean, Martin Forster, Amanda Farley, Dee Wherton, Manita Mehmi, Rowena Sharpe, Tara C Mills, Maria Antonietta Cerone, Timothy A Yap, Thomas B K Watkins, Emilia Lim, Charles Swanton, Lucinda Billingham
• Journal: Nature (Nature) Vol. 583 Issue 7818 Pg. 807-812 (07 2020) ISSN: 1476-4687 [Electronic] England
• PMID: 32669708 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Genetic Markers
• Smoke

Topics

• Bayes Theorem
• Carcinoma, Non-Small-Cell Lung (etiology, genetics, therapy)
• Clinical Protocols
• Clinical Trials as Topic
• Cohort Studies
• Genetic Markers
• Genotype
• High-Throughput Nucleotide Sequencing
• Humans
• Lung Neoplasms (etiology, genetics, therapy)
• Molecular Targeted Therapy
• Oncogenes (genetics)
• Patient Selection
• Precision Medicine
• Smoke (adverse effects)
• Smoking (genetics)
• Triage