Abstract PL03-03: The National Lung Matrix Trial (NLMT): Challenges and opportunities

Abstract

Abstract The National Lung Matrix Trial (NLMT) is a CR-UK funded national umbrella trial in advanced non-small cell lung cancer (NSCLC), exploring the activity of a number of targeted agents in molecularly stratified patients. Currently, biomarker identification is performed on a bespoke 28-gene next-generation sequencing panel (The Stratified Medicine Programme-2) using surplus FFPE diagnostic tissue. The primary aim of the trial is to detect signals of activity, either objective response or durable stabilizations, to thus provide robust stop-go decisions for the further clinical and translational development of promising biomarker:drug combinations, using a Bayesian statistical design. Actionability of genetic aberrations is called using a comprehensive tiering system, and preclinical data inform a number of key molecular exclusion rules for selected biomarkers in order to enrich for patients likely to obtain therapeutic benefit. The requirement for confident wild-type calling of these molecular exclusions results in an attrition of up to 1/3 of patients who harbor suitable molecular biomarkers due to a failure to achieve the required read depth, and the reasons for this and the strategies used to mitigate against this problem will be discussed. The transition rate of patients screened to patients allocated is around 6%, and the causes of this second level of attrition will be reviewed together with the implications this has for running precision medicine trials, particularly in small biomarker-selected cohorts and, moreover, in an era of immunotherapy. The trial and platform is adaptive, allowing the integration of emerging preclinical and clinical data into currently running cohorts and the development of new biomarker:drug cohorts, and several new cohorts will be initiated in the next 65 months. Key translational endpoints include longitudinal ctDNA analysis and the development of PDX models to determine supplemental predictive biomarkers and mechanisms of resistance. The molecular eligibility rate is around 35%, and currently we have allocated 178 patients to one of 20 open cohorts, trailing 7 targeted drugs. Outcome data from several important cohorts will be presented next year. The overlap and complementarity of NLMT with similar programs, notably LUNG-MAP and NCI-MATCH, suggests that global coordination of national precision-medicine programs will significantly accelerate the identification of any remaining oncogene addictions and of molecularly targeted strategies that provide robust deflection of the natural history of selected patients with advanced NSCLC, the selection of the best drug target and drug for each aberration, and the strategies that might be employed to limit the emergence of resistance. (For and on behalf of The Stratified Medicine Programme-2 working party and the NLMT Consortium.) Citation Format: Gary Middleton. The National Lung Matrix Trial (NLMT): Challenges and opportunities [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr PL03-03.