Abstract
PURPOSETherapeutically 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 METHODSTumor 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.RESULTSMolecular 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.CONCLUSIONWe 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.
Highlights
The first targeted therapy successes in oncogenedriven cancers were specific to single cancer histologies
Actionability rates differed among histologies
National Cancer Institute (NCI)-MATCH opened on August 12, 2015; 1,117 sites registered 6,391 patients until registration for centralized molecular screening closed on May 22, 2017 (Data Supplement)
Summary
The first targeted therapy successes in oncogenedriven cancers were specific to single cancer histologies (eg, BCR-ABL translocations in chronic myelogenous leukemia[1]; ERBB2 gene amplification in breast cancer[2]; BRAF mutations in melanoma[3]; and EGFR mutations and ALK translocations in lung adenocarcinoma[4,5]). BRAF-inhibitor therapy was explored across a spectrum of BRAF-mutated cancers and yielded high response rates in melanoma, non–small-cell lung cancer (NSCLC), and Langerhans cell histiocytosis but unanticipated resistance in colorectal cancer, despite ample preclinical evidence favoring efficacy.[6,7] More recently, the US Food and Drug Administration (FDA) has approved the programmed death-1 inhibitor pembrolizumab for any patient with mismatch repair deficiency and high microsatellite instability. This abnormality occurs in approximately 2% of patients.[8,9] Larotrectinib was approved for any patient whose tumor harbors a neurotrophic tropomyosin receptor kinase (NTRK) fusion, which, common in several rare tumors, occurs in , 1% of most tumor histologies.[10,11]
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