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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 smoke^1-3. 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.

SUBMITTER: Middleton G

PROVIDER: S-EPMC7116732 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Middleton Gary G Fletcher Peter P Popat Sanjay S Savage Joshua J Summers Yvonne Y Greystoke Alastair A Gilligan David D Cave Judith J O'Rourke Noelle N Brewster Alison A Toy Elizabeth E Spicer James J Jain Pooja P Dangoor Adam A Mackean Melanie M Forster Martin M Farley Amanda A Wherton Dee D Mehmi Manita M Sharpe Rowena R Mills Tara C TC Cerone Maria Antonietta MA Yap Timothy A TA Watkins Thomas B K TBK Lim Emilia E Swanton Charles C Billingham Lucinda L

Nature 20200715 7818

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 smoke<sup>1-3</sup>. 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 ...[more]

PMID: 32669708

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Project description:Background Subsolid pulmonary nodules, comprising pure ground-glass nodules (GGNs) and part-solid nodules (PSNs), have a high risk of indolent malignancy. Lung Imaging Reporting and Data System (Lung-RADS) nodule management guidelines are based on expert opinion and lack independent validation. Purpose To evaluate Lung-RADS estimates of the malignancy rates of subsolid nodules, using nodules from the National Lung Screening Trial (NLST), and to compare Lung-RADS to the NELSON trial classification as well as the Brock University calculator. Materials and Methods Subsets of GGNs and PSNs were selected from the NLST for this retrospective study. A thoracic radiologist reviewed the baseline and follow-up CT images, confirmed that they were true subsolid nodules, and measured the nodules. The primary outcome for each nodule was the development of malignancy within the follow-up period (median, 6.5 years). Nodules were stratified according to Lung-RADS, NELSON trial criteria, and the Brock model. For analyses, nodule subsets were weighted on the basis of frequency in the NLST data set. Nodule stratification models were tested by using receiver operating characteristic curves. Results A total of 622 nodules were evaluated, of which 434 nodules were subsolid. At baseline, 304 nodules were classified as Lung-RADS category 2, with a malignancy rate of 3%, which is greater than the 1% in Lung-RADS (P = .004). The malignancy rate for GGNs smaller than 10 mm (two of 129, 1.3%) was smaller than that for GGNs measuring 10-19 mm (11 of 153, 6%) (P = .01). The malignancy rate for Lung-RADS category 3 was 14% (13 of 67), which is greater than the reported 2% in Lung-RADS (P < .001). The Brock model predicted malignancy better than Lung-RADS and the NELSON trial scheme (area under the receiver operating characteristic curve = 0.78, 0.70, and 0.67, respectively; P = .02 for Brock model vs NELSON trial scheme). Conclusion Subsolid nodules classified as Lung Imaging Reporting and Data System (Lung-RADS) categories 2 and 3 have a higher risk of malignancy than reported. The Brock risk calculator performed better than measurement-based classification schemes such as Lung-RADS. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Kauczor and von Stackelberg in this issue.

Dataset Information

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

Publications

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

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