BACKGROUND The proportion of tumors of various histologies that may respond to drugs targeted to molecular alterations is unknown. NCI-MATCH, a collaboration between ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) and the National Cancer Institute (NCI), was initiated to find efficacy signals by matching patients with refractory malignancies to treatment targeted to potential tumor molecular drivers regardless of cancer histology. METHODS Trial development required assumptions about molecular target prevalence, accrual rates, treatment eligibility, enrollment rates, as well as consideration of logistical requirements. Central tumor profiling was performed with an investigational Next Generation DNA targeted Sequencing assay (NGS) of alterations in 143 genes, and protein expression of PTEN, MLH1, MSH2 and Rb. Treatments were allocated with a validated computational platform (MATCHBOX). A pre-planned interim analysis evaluated assumptions and feasibility in this novel trial. RESULTS At interim analysis, accrual was robust, tumor biopsies were safe (< 1% severe events), and profiling success was 87.3%. Actionable molecular alteration frequency met expectations, but assignment and enrollment lagged due to histology exclusions and mismatch of resources to demand. To address this lag, we revised estimates of mutation frequencies, increased screening sample size, added treatments and improved assay throughput and efficiency (93.9% completion and 14-day turnaround). CONCLUSIONS The experiences in the design and implementation of the NCI-MATCH trial suggest that profiling from fresh tumor biopsies and assigning treatment can be performed efficiently in a large national network trial. The success of such trials necessitates a broad screening approach and many treatment options easily accessible to patients.

中文翻译：

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治疗选择（NCI-MATCH）试验的分子分析：基因组试验设计的教训。

背景 可能对靶向分子改变的药物有反应的各种组织学的肿瘤的比例是未知的。NCI-MATCH 是 ECOG-ACRIN 癌症研究小组 (ECOG-ACRIN) 和美国国家癌症研究所 (NCI) 之间的合作项目，旨在通过将难治性恶性肿瘤患者与针对潜在肿瘤分子驱动因素的治疗进行匹配来寻找疗效信号，而不管癌症如何组织学。方法 试验开发需要对分子靶标流行率、应计率、治疗资格、入组率以及后勤要求的考虑做出假设。使用研究性下一代 DNA 靶向测序分析 (NGS) 对 143 个基因的改变以及 PTEN、MLH1、MSH2 和 Rb 的蛋白质表达进行中心肿瘤分析。使用经过验证的计算平台（MATCHBOX）分配治疗。一项预先计划的中期分析评估了这项新试验的假设和可行性。结果 在中期分析中，应计结果稳健，肿瘤活检安全（< 1% 严重事件），分析成功率为 87.3%。可操作的分子改变频率符合预期，但由于组织学排除和资源与需求不匹配，分配和登记滞后。为了解决这一滞后问题，我们修改了突变频率的估计值、增加了筛选样本量、增加了治疗方法并提高了检测通量和效率（93.9% 的完成率和 14 天的周转时间）。结论 NCI-MATCH 试验的设计和实施经验表明，可以在大型国家网络试验中有效地进行新鲜肿瘤活检的分析和分配治疗。此类试验的成功需要广泛的筛查方法和患者容易获得的许多治疗选择。