TY - JOUR
T1 - The National Lung Matrix Trial of personalized therapy in lung cancer
AU - Middleton, Gary
AU - Fletcher, Peter
AU - Popat, Sanjay
AU - Savage, Joshua
AU - Summers, Yvonne
AU - Greystoke, Alastair
AU - Gilligan, David
AU - Cave, Judith
AU - O’Rourke, Noelle
AU - Brewster, Alison
AU - Toy, Elizabeth
AU - Spicer, James
AU - Jain, Pooja
AU - Dangoor, Adam
AU - Mackean, Melanie
AU - Forster, Martin
AU - Farley, Amanda
AU - Wherton, Dee
AU - Mehmi, Manita
AU - Sharpe, Rowena
AU - Mills, Tara C.
AU - Cerone, Maria Antonietta
AU - Yap, Timothy A.
AU - Watkins, Thomas B.K.
AU - Lim, Emilia
AU - Swanton, Charles
AU - Billingham, Lucinda
N1 - Funding Information:
Competing interests 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.
Funding Information:
Acknowledgements The Investigators and Sponsor thank all the patients and their families who participated in this trial, as well as the NHS Trusts and staff and the members of the Trial Steering Committee, chaired by R. Kaplan, who have supported this trial. We thank our patient and public representatives, M. Baker on the Trial Steering Committee and T. Haswell on the Trial Management Group. This is an investigator-initiated and investigator-led trial funded by CRUK grant C11497/A19363 and C11497/A22209. Trial drugs were supplied free of charge by AstraZeneca (AZD4547, vistusertib, selumetinib, capivasertib, osimertinib and durvalumab), Pfizer (palbociclib and crizotinib) and Mirati (sitravatinib), who also supported the programme through the funding of SMP2. The Cancer Research UK Clinical Trials Unit at the University of Birmingham is supported by CRUK grant C22436/A25354. The National Lung Matrix Trial was supported by Experimental Cancer Medicine Centres (ECMC) funding and by the ECMC Network. This trial has been independently peer reviewed and has been adopted by the National Institute for Health Research Clinical Research Network Portfolio.
Funding Information:
Thetrialcompliedwithallregulatoryrequirements;ethicalapproval for the trial protocol (currently v.8.0, dated 18 October 2019) was obtained from South Central - Oxford C Research Ethics Committee and clinical trial authorization was granted by UK Medicines and Healthcare products Regulatory Agency (MHRA). The trial was sponsored by the University of Birmingham and run by the Cancer Research UK Clinical Trials Unit located there. Funding for the trial came from Cancer Research UK with drugs provided by pharmaceutical partners. The trial was initiated and conducted independently by the trial investigators in collaboration with Cancer Research UK. The corresponding author had full access to all the data in the trial and had final responsibility for the decision to submit for publication. The independent Trial Steering Committee reviewed the interim data every 6 months to ensure patient safety and are responsible for making decisions to close cohorts early and to share interim data with investigators and pharmaceutical industry partners. In particular, they endorsed the decision to publish the interim data.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/7/30
Y1 - 2020/7/30
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85087956964&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85087956964&partnerID=8YFLogxK
U2 - 10.1038/s41586-020-2481-8
DO - 10.1038/s41586-020-2481-8
M3 - Article
C2 - 32669708
AN - SCOPUS:85087956964
SN - 0028-0836
VL - 583
SP - 807
EP - 812
JO - Nature
JF - Nature
IS - 7818
ER -