@article{5bb066346322499e9977a4bca57469ba,
title = "Molecular landscape and actionable alterations in a genomically guided cancer clinical trial: National cancer institute molecular analysis for therapy choice (NCI-MATCH)",
abstract = "PURPOSE Therapeutically actionable molecular alterations are widely distributed across cancer types. The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial was designed to evaluate targeted therapy antitumor activity in underexplored cancer types. Tumor biopsy specimens were analyzed centrally with next-generation sequencing (NGS) in a master screening protocol. Patients with a tumor molecular alteration addressed by a targeted treatment lacking established efficacy in that tumor type were assigned to 1 of 30 treatments in parallel, single-arm, phase II subprotocols. PATIENTS AND METHODS Tumor biopsy specimens from 5,954 patients with refractory malignancies at 1,117 accrual sites were analyzed centrally with NGS and selected immunohistochemistry in a master screening protocol. The treatment-assignment rate to treatment arms was assessed. Molecular alterations in seven tumors profiled in both NCI-MATCH trial and The Cancer Genome Atlas (TCGA) of primary tumors were compared. RESULTS Molecular profiling was successful in 93.0% of specimens. An actionable alteration was found in 37.6%. After applying clinical and molecular exclusion criteria, 17.8% were assigned (26.4% could have been assigned if all subprotocols were available simultaneously). Eleven subprotocols reached their accrual goal as of this report. Actionability rates differed among histologies (eg,. 35% for urothelial cancers and, 6% for pancreatic and small-cell lung cancer). Multiple actionable or resistance-conferring tumor mutations were seen in 11.9% and 71.3% of specimens, respectively. Known resistance mutations to targeted therapies were numerically more frequent in NCI-MATCH than TCGA tumors, but not markedly so. CONCLUSION We demonstrated feasibility of screening large numbers of patients at numerous accruing sites in a complex trial to test investigational therapies for moderately frequent molecular targets. Co-occurring resistance mutations were common and endorse investigation of combination targeted-therapy regimens.",
author = "{NCI-MATCH team} and Flaherty, {Keith T.} and Gray, {Robert J.} and Chen, {Alice P.} and Shuli Li and McShane, {Lisa M.} and David Patton and Hamilton, {Stanley R.} and {Mickey Williams}, P. and {John Iafrate}, A. and Jeffrey Sklar and Mitchell, {Edith P.} and Harris, {Lyndsay N.} and Naoko Takebe and Sims, {David J.} and Brent Coffey and Tony Fu and Mark Routbort and Zwiebel, {James A.} and Rubinstein, {Larry V.} and Little, {Richard F.} and Arteaga, {Carlos L.} and Robert Comis and Abrams, {Jeffrey S.} and O'Dwyer, {Peter J.} and Conley, {Barbara A.}",
note = "Funding Information: This study involved close collaboration between the National Cancer Institute (NCI), which funded the study and provided expertise and access to drugs, and the ECOG-ACRIN Cancer Research Group and other members of the National Clinical Trials Network in the design and conduct of the trial under the award numbers listed in the funding statement. NCI-MATCH committees enlisted clinical and translational researchers, pathologists, and scientists (especially with genomic analysis and interpretation expertise), operations experts, patient advocates, and patients with cancer. Industry engagement, through the well-defined structure the NCI provides, was critical to obtaining well-credentialed drugs for the treatment sub-protocols. Special recognition goes to the Frederick National Laboratory Bioinformatics/Data Science Group, led by Anjan Purkayastha and Anna Steinfeld, for generating the figures featured in this manuscript. The results published here are in part based on data generated by The Cancer Genome Atlas (TCGA; phs000178.v10.p8) managed by NCI and National Human Genome Research Institute. Information about TCGA can be found at http:// cancergenome.nih.gov. Funding Information: Supported by the National Cancer Institute (Grants No. U10CA180820 [R.C.]; U10CA180794 [R.J.G.]; UG1CA233341 [E.P.M.]; UG1CA233180; UG1CA233302; UG1CA233329; and UG1CA233337). Publisher Copyright: {\textcopyright} 2020 by American Society of Clinical Oncology",
year = "2020",
month = nov,
day = "20",
doi = "10.1200/JCO.19.03010",
language = "English (US)",
volume = "38",
pages = "3883--3894",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "33",
}