PURPOSE TRK inhibitors achieve marked tumor-agnostic efficacy in TRK fusion-positive cancers and consequently are now an established standard of care. Little is known, however, about the demographics, outcomes, response to alternative standard therapies, or genomic characteristics of TRK fusion-positive cancers. EXPERIMENTAL DESIGN Utilizing a center-wide screening program involving more than 26,000 prospectively sequenced patients, genomic and clinical data from all cases with TRK fusions were extracted. An integrated analysis was performed of genomic, therapeutic, and phenomic outcomes. RESULTS We identified 76 cases with confirmed TRK fusions (0.28% overall prevalence) involving 48 unique rearrangements and 17 cancer types. The presence of a TRK fusion was associated with depletion of concurrent oncogenic drivers (P < 0.001) and lower tumor mutation burden (P < 0.001), with the exception of colorectal cancer where TRK fusions cooccur with microsatellite instability (MSI-H). Longitudinal profiling in a subset of patients indicated that TRK fusions were present in all sampled timepoints in 82% (14/17) of cases. Progression-free survival on first-line therapy, excluding TRK inhibitors, administered for advanced disease was 9.6 months [95% confidence interval (CI), 4.8-13.2]. The best overall response rate achieved with chemotherapy containing-regimens across all lines of therapy was 63% (95% CI, 41-81). Among 12 patients treated with checkpoint inhibitors, a patient with MSI-H colorectal cancer had the only observed response. CONCLUSIONS TRK fusion-positive cancers can respond to alternative standards of care, although efficacy of immunotherapy in the absence of other predictive biomarkers (MSI-H) appears limited. TRK fusions are present in tumors with simple genomes lacking in concurrent drivers that may partially explain the tumor-agnostic efficacy of TRK inhibitors.

中文翻译：

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TRK Fusions富含组织学罕见且缺乏典型驾驶员突变的癌症。

用途TRK抑制剂在TRK融合阳性癌症中具有显着的肿瘤不可知功效，因此现在已成为公认的护理标准。然而，关于TRK融合阳性癌症的人口统计学，结果，对替代标准疗法的反应或基因组特征知之甚少。实验设计利用一项涉及26,000多名预期测序患者的全中心筛查计划，从所有TRK融合病例中提取基因组和临床数据。对基因组，治疗和表型结果进行了综合分析。结果我们确定了76例确诊TRK融合的病例（总患病率0.28％），涉及48种独特的重排和17种癌症类型。TRK融合的存在与并发致癌驱动因子的耗竭有关（P <0。001）和较低的肿瘤突变负担（P <0.001），大肠癌除外，因为TRK融合与微卫星不稳定性同时发生（MSI-H）。在部分患者中进行的纵向分析表明，在82％（14/17）的病例中，所有采样时间点都存在TRK融合。对于晚期疾病，一线治疗（不包括TRK抑制剂）的无进展生存期为9.6个月[95％置信区间（CI），4.8-13.2]。在所有治疗方案中，含化疗方案的化疗均能获得最佳的总体缓解率（63％（95％CI，41-81））。在接受检查点抑制剂治疗的12例患者中，只有MSI-H大肠癌患者有观察到的反应。结论TRK融合阳性癌症可以对替代治疗标准做出反应，尽管在缺乏其他预测性生物标志物（MSI-H）的情况下免疫疗法的疗效似乎有限。TRK融合蛋白存在于简单基因组缺乏并行驱动程序的肿瘤中，这可能部分解释了TRK抑制剂的肿瘤不可知功效。