Abstract Oncology has undergone major changes in systemic treatment options, from chemotherapy to antiangiogenic agents to tyrosine-kinase inhibitors to immunotherapy. Historically, a therapeutic agent is tested in separate trials as monotherapy or combined with investigational or approved agents/modalities, to determine antitumor activity in each histology based on the premise that each histology responds differently to the same treatment. This paradigm is time consuming and may or may not make use of molecular characterization to test each agent in each histology. However, with the expansion of biologic understanding and development of various biomarkers, e.g., estrogen receptor and Her 2 amplification, we move beyond the basic paradigm of general histology to one in which treatment is based upon molecular characteristics of the tumor. Examples of recent discoveries from this more modern paradigm are (1) multiple histologies sharing a common molecular profile and (2) a subset within a single histology having a given molecular characteristic. Various agents have been tested singularly in terms of molecular aberrations and histology, e.g., ALK inhibitors and NSCLC. However, with the rapid increase in the number of targeted agents in development, more facile and efficient clinical trial designs are needed. The National Cancer Institute (NCI) and ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) collaborated in designing the Molecular Analysis for Therapy Choice trial (NCI-MATCH or EAY131), the first large-scale signal-finding precision medicine oncology trial in the United States to incorporate centralized NGS testing to direct patients to parallel (nonrandomized) phase II treatment arms under a master protocol. The trial is being conducted by the NCI National Clinical Trials Network (NCTN), with ECOG-ACRIN leading the trial. More than 100 investigators from across the NCTN adult cancer-oriented member groups (Alliance for Clinical Trials in Oncology, ECOG-ACRIN, NRG Oncology, and SWOG) have worked collaboratively to design and lead what is currently 30 treatment arms (subprotocols), with more arms in development. Wide-scale NCTN investigator involvement ensures use of the latest knowledge to define the actionable mutations required for eligibility and to make evidence-based selections of experimental agents. In NCI-MATCH, patients are assigned treatment based on the genomic alterations found in their tumors through genomic sequencing and other tests at the time of initial enrollment for screening. Unlike other phase II trials, each arm is open to advanced solid tumors, lymphomas, or myeloma that share a set of molecular aberrations, not restricted to a single histology. This strategy accommodates and encourages enrollment of rare tumors for which there are often no standard treatments and limited clinical trial options. NCI-MATCH has 10-30 concurrent treatment arms available to patients at any given time, testing both investigational agents and FDA-approved drugs for new indications. Most treatment arms have an enrollment goal of 35 patients, with some arms that address tumor gene variants of higher prevalence expanded to 70 patients. Together, the NCTN and NCI Community Oncology Research Program provide infrastructure for many clinical sites (>1100) to participate, providing ready access to physicians and patients; screening enrollment has occurred in all 50 states in the U.S, the District of Columbia, and Puerto Rico. A specific assay was developed for the trial (the MATCH assay), and a laboratory network was organized to rapidly process the tissue and efficiently interrogate for mutations. NCI and ECOG-ACRIN statisticians developed the analysis plan and are currently maintaining data that are closely monitored by safety experts for any adverse event signals. Lastly, a bioinformatics system (MATCHbox) was developed to coordinate molecular data collection and support rule-based decision-making based on those data. Because genomics in oncology is rapidly expanding and evolving, NCI-MATCH required flexibility to accommodate brisker screening accrual than anticipated, and adaptation to constantly emerging information about new drugs and new molecular alterations. The goal to sequence the tumors of 6,000 patients with NCI funding was achieved two years ahead of schedule, but that cohort was not sufficient to fill all the arms—in particular, those aimed at the most rarely occurring tumor gene aberrations. Currently, the goal for the trial is to complete the open treatment arms by allowing for designated commercial and academic laboratories to notify ordering physicians when genomic tests they ordered to guide clinical care indicate a potential eligibility to a NCI-MATCH arm with a rare variant and allow for enrollment to the relevant treatment subprotocol if the patient meets all subprotocol eligibility criteria. The tissue confirmation of the molecular abnormality on the MATCH assay by the central laboratories will be accomplished after subprotocol enrollment so that patient treatment will not be delayed for confirmation. A demonstration project is now under way to test the applicability of this approach and potentially develop common standards for future use. With tumor sequencing becoming a more and more common practice in oncology, this may allow patients with mutations of low prevalence to have investigational treatment options. NCI-MATCH is expanding its panel and definition of actionable mutations to allow greater flexibility to incorporate in real time new mutations supported with adequate levels of evidence. The valuable genomic and clinical outcome data collected in the trial will permit evaluation of efficacy of targeting certain actionable mutations with a specific agent. In addition, biospecimens are being collected to build a rich resource for conducting auxiliary biology studies that may answer questions about prevalence of mutations in the metastatic setting, prevalence of mutations in rare histologies, and resistance mechanisms of various targeted therapy. At this meeting, two abstracts will provide an overall trial update and present information about the prevalence of mismatch repair deficiency (dMMR) in the centrally screened population. Citation Format: Alice P. Chen, Peter J. O'Dwyer, Lyndsay Harris, Barbara A. Conley, Stanley R. Hamilton, Mickey Williams, Robert J. Gray, Shuli Li, Lisa M. McShane, Lawrence V. Rubinstein, Susanna I. Lee, Shaji Kumar, Edith P. Mitchell, James A. Zwiebel, Constantine A. Gatsonis, Lalitha K. Shankar, Paolo F. Caimi, Carlos L. Arteaga, A John Iafrate, Jeffrey Sklar, Richard F. Little, Keith T. Flaherty. NCI-MATCH: A new paradigm in the era of genomic oncology [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 PL03-01.