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The National Lung Matrix Trial of personalized therapy in lung cancer
Gary Middleton1,2, Peter Fletcher3, Sanjay Popat4
1Institute of Immunology & Immunotherapy, University of Birmingham, Birmingham, UK. g.middleton@bham.ac.uk.
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.
Insights
Targeted therapies for non-small cell lung cancer (NSCLC) show limited benefit in tobacco-associated cases. The National Lung Matrix Trial found few drug-biomarker combinations effective, primarily in patients with minimal tobacco exposure.
Area of Science:
- Oncology
- Genomics
- Clinical Trials
Background:
- Targeted therapies for non-small cell lung cancer (NSCLC) primarily benefit patients with oncogenic drivers less common in smokers.
- Developing stratified medicine for tobacco-associated NSCLC is a critical unmet need.
- Umbrella trials efficiently investigate multiple genotype-matched treatments by screening tumors for various genomic alterations.
Purpose of the Study:
- To report outcomes from the National Lung Matrix Trial, a large umbrella trial for NSCLC.
- To evaluate the effectiveness of drug-biomarker combinations identified through next-generation sequencing.
- To assess the clinical utility of genotype-matched therapies in a diverse NSCLC patient population.
Main Methods:
- Utilized next-generation sequencing to identify tumor genotypes for patient matching.
- Screened 5,467 patients, with 2,007 found molecularly eligible for the trial.
- Employed a Bayesian trial design to integrate data from ongoing and completed cohorts.
Main Results:
- 302 patients received genotype-matched therapy within the 19 drug-biomarker cohorts.
- Despite pre-clinical rationale, few drug-biomarker combinations demonstrated clinically relevant benefits.
- Effective treatments were predominantly observed in patients with NSCLC associated with minimal tobacco smoke exposure.
Conclusions:
- Current umbrella trial data suggest limited clinical benefit from many tested drug-biomarker combinations in NSCLC.
- The efficacy of targeted therapies in this trial remains concentrated in non-smokers or those with minimal tobacco exposure.
- Further research is needed to identify effective stratified treatments for tobacco-associated NSCLC.
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