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.This article is available to RD&E staff via NHS OpenAthens (subject to publisher embargo). Click on the Publisher URL, and log in with NHS OpenAthens if prompted.G.M. reported receiving research funding from Bristol-Myers Squibb, Kael-Gemvax, Merck Sharp & Dome and Plexxikon, and personal fees from BioLineRx, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dome and Roche. S.P. reported receiving research funding from Boehringer Ingelheim, Epizyme, Bristol-Myers Squibb, Clovis Oncology, Roche, Eli Lilly and Takeda, and personal fees from Boehringer Ingelheim, AstraZeneca, Roche, Takeda, Chugai Pharma, Merck Sharp & Dohme, Bristol-Myers Squibb, EMD Serono, Abbvie, Guardant Health, Pfizer and Novartis. J. Savage reported receiving personal fees from Eli Lilly. Y.S. reported personal fees from Roche, AstraZeneca, Takeda, Pfizer and Merck Sharp & Dohme. A.G. reported personal fees from Pfizer, Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, AstraZeneca, Bristol-Myers Squibb, Takeda, Abbvie, Roche and Foundation Medicine. D.G. reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Genesis Care UK, Pfizer, Roche, Takeda and Merck Sharp & Dohme and non-financial competing interests with Roy Castle Lung Cancer Foundation. E.T. reported receiving personal fees from Roche, Pfizer, Boehringer Ingelheim and Merck Sharp & Dohme. J. Spicer reported receiving research funding from Starpharma, Taiho Pharmaceutical, Bristol-Myers Squibb, Roche, BerGenBio,Genmab and Curis, personal fees from Bristol-Myers Squibb, Lytix Biopharma and IObiotech and owning stocks and shares in IGEA. P.J. reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly and Pfizer. T.Y. reported research funding from AstraZeneca, Vertex, Pfizer, Bayer, Tesaro, Jounce Therapeutics, Eli Lilly, Seattle Genetics, Kyowa Hakko Kirin, Constellation Pharmaceuticals and personal fees from AstraZeneca, Pfizer, Tesaro, EMD Serono, Vertex, Seattle Genetics, Roche, Janssen, Clovis Oncology, Ignyta, Atrin Pharmaceuticals, Aduro Biotech, Merck Sharp & Dohme, Almac Group, Bayer, Bristol-Myers Squibb, Calithera Biosciences and Cybrexa Therapeutics. C.S. reports receiving research funding from Boehringer Ingelheim and personal fees from Genentech, Roche, Sarah Cannon Research Institute, Boehringer Ingelheim, GlaxoSmithKline, Eli Lilly, Celgene, Ono Pharmaceutical, SERVIER, Pfizer, Bristol-Myers Squibb, Novartis, AstraZeneca and Ilumina and owning stocks and shares in Epic Sciences, Apogen Biotechnologies, GRAIL and Achilles Therapeutics. J.C. reported receiving personal fees from Novartis, Eli Lilly and Boehringer Ingelheim. A.F. reported receiving research funding from Ethicon (Johnson and Johnson). R.S., T.C.M. and M.C. were employed by Cancer Research UK who fund the study. L.B. reports receiving personal fees from AstraZeneca, Novartis and Springer. The other authors declare no competing interests.accepted version (6 month embargo), submitted versio