Results from Large-Scale NSCLC Precision Medicine Trial Inform Future Trial Design

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Lung Cancer
[Credit: Lee Health]

New data from the National Lung Matrix Trial (NLMT) in non-small cell lung cancer (NSCLC) highlights key factors for successful design of precision medicine trials. This most current NLMT study focused on patients with light exposure to tobacco smoke. These represent about 20% of lung cancer patients, but their tumors are more likely to carry oncogenic drivers, which also makes them more likely to respond to targeted therapies. There is great interest in determining the best ways to match such patients to therapies. There are currently over 800 clinical trials of NSCLC therapies with biomarkers, according to Clinicaltrials.gov.

The NLMT was launched as a £25 million collaboration with Pfizer, AstraZeneca, and other pharmaceutical companies, and with support from the NHS. The project uses next generation sequencing (NGS) to match treatments to patients based on genetic markers. This latest NLMT paper was published in Nature this week. https://www.nature.com/articles/s41586-020-2481-8

Patients enrolled in the NLMT are genetically screened by the Cancer Research UK SMP2 to understand more about their tumor type, and whether they possess the relevant genetic signatures to be matched to a targeted treatment. Since the trial opened to recruitment in May 2015 until November 2019, 288 patients were recruited to the 19 targeted treatment cohorts on the trial.

These latest results revealed key learnings on the use of precision medicine. These included insights on: how the appropriate pre-clinical work is essential in defining appropriate biomarker-drug combinations to test in the clinic, how to ensure the best drugs available are used to hit the genomic targets, managing the scale of attrition from large screening platforms, and the importance of analyzing and publishing outcome data of an ongoing study.

For example, the attrition rate in his study was high with only a 5% of SMP2 patients receiving treatment. Targeted therapy trials should take place as early as possible in the cancer journey and use blood based genomic testing for fast turn-round of the information. However, discussions about trials often come towards the end of the patient’s journey.

Lead author of the NLMT study, Professor Gary Middleton, Medical Oncologist at the University of Birmingham said: “This study provides data on how the next wave of trialling [trials using] targeted therapies to treat complex cancers should be designed. This is the first trial of its kind, the novel Bayesian design allows outcome data from open cohorts that are still recruiting to be reported alongside closed cohorts, whereas previous umbrella studies have only published the results of completed arms and cohorts.

“We found genomically complicated tumours are hard to treat with targeted therapy, especially with monotherapy. The models we test drugs on are too simplistic – they don’t represent the genomic complexity of the tumour, or the trajectory of how they rapidly evolve. We need models that take into account the complexity and trajectory of a human tumour to decide if a drug is going to work.”

Ian Walker, Director of Research at Cancer Research UK said: “The National Lung Matrix trial is a flagship programme for Cancer Research UK and continues to provide significant insights into how we should treat genomically diverse cancers, such as lung. Not only will it shape the thinking for future studies delivering complex precision medicines, but it has also demonstrated how molecular diagnostic testing and clinical research can work in a truly integrated manner within the National Health Service across the UK to allow patients to access the latest new treatments.”

Next steps in the NLMT are to continue recruiting patients. There will also be further publications from the individual arms and cohorts, and translational laboratory work.

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