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Levels of Evidence for Prioritization of Actionable Molecular Abnormalities in the NCI-MATCHTrial TA B L E 1 5 . 1 Level 1: Gene variant credentialed for a U.S. Food and Drug Administration–approved drug Level 2: Molecular characteristic is an eligibility criterion for an ongoing clinical trial utilizing that drug or the abnormality has been identified in an N-of-1 clinical response Level 3: Preclinical response: (1) models with variant respond while models without abnormality do not, (2) gain-of-function mutation demonstrated in a preclinical model, (3) loss of function in a preclinical model (tumor suppressor gene or pathway inhibitor) NCI-MATCH, National Cancer Institute Molecular Analysis for Therapy Choice. Adapted from Conley BA, Doroshow JH. Molecular Analysis for Therapy Choice: NCI MATCH. Semin Oncol 2014;41:297–299.

Umbrella trials may also be histology independent and focus on multiple drug targets across a broad array of malignancies. Although such studies are most often signal-seeking/hypothesis-generating endeavors that are unlikely, despite their large size, to facilitate FDA approval of a specific mutation/biomarker pair and are resource intensive, they are a major avenue for evaluating the role of treating patients who harbor tumors that express low-preva- lence mutations with targeted therapeutics. Screening large num- bers of patients to be treated for a broad range of molecular targets with a large formulary of drugs also decreases the failure rate of mutational screening, improving the chance that patients will re- ceive treatment on study. The largest of such efforts is the NCI Molecular Analysis for Therapy Choice (MATCH) trial, overseen for the NCI’s National Clinical Trials Network by the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network (ECOG-ACRIN) group. 21 This study, with the trial schema shown in Figure 15.4, has reached the goal of its ini- tial phase of accrual; approximately 6,400 patients were enrolled and had fresh biopsies of metastatic sites at over 1,000 participating

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Figure 15.4  Schema for the National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) clinical trial. The NCI-MATCH clinical trial is an umbrella study to examine the hypothesis that treating adult solid tumors and lymphomas with molecularly targeted therapies independent of disease histology can be effective. Over 6,000 patients have been accrued at over 1,000 clinical trial sites; patients underwent fresh tumor biopsies for next-generation sequencing by a centralized laboratory network. A formulary of over 30 drugs from a wide range of pharmaceutical firms permitted accrual of patients with low-prevalence mutations to a series of phase II investigations.