Tumor-agnostic therapies represent a paradigm shift in oncology by altering the traditional means of characterizing tumors based on their origin or location. Instead, they zero in on specific genetic anomalies responsible for fueling malignant growth. The watershed moment for tumor-agnostic therapies arrived in 2017, with the US Food and Drug Administration's historic approval of pembrolizumab, an immune checkpoint inhibitor. This milestone marked the marriage of genomics and immunology fields, as an immunotherapeutic agent gained approval based on genomic biomarkers, specifically, microsatellite instability-high or mismatch repair deficiency (dMMR). Subsequently, the approval of NTRK inhibitors, designed to combat NTRK gene fusions prevalent in various tumor types, including pediatric cancers and adult solid tumors, further underscored the potential of tumor-agnostic therapies. The US Food and Drug Administration approvals of targeted therapies (BRAF V600E, RET fusion), immunotherapies (tumor mutational burden ≥10 mutations per megabase, dMMR) and an antibody-drug conjugate (Her2-positive–immunohistochemistry 3+ expression) with pan-cancer efficacy have continued, offering newfound hope to patients grappling with advanced solid tumors that harbor particular biomarkers. In this comprehensive review, the authors delve into the expansive landscape of tissue-agnostic targets and drugs, shedding light on the rationale underpinning this approach, the hurdles it faces, presently approved therapies, voices from the patient advocacy perspective, and the tantalizing prospects on the horizon. This is a welcome advance in oncology that transcends the boundaries of histology and location to provide personalized options.

中文翻译：

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精准肿瘤学中组织不可知疗法的不断发展


肿瘤不可知论疗法通过改变基于肿瘤起源或位置来表征肿瘤的传统方法，代表了肿瘤学的范式转变。相反，他们将注意力集中在导致恶性生长的特定遗传异常上。 2017 年，美国食品和药物管理局历史性地批准了免疫检查点抑制剂派姆单抗 (pembrolizumab)，肿瘤不可知疗法的分水岭到来了。这一里程碑标志着基因组学和免疫学领域的联姻，因为一种免疫治疗剂获得了基于基因组生物标志物的批准，特别是微卫星不稳定性高或错配修复缺陷（dMMR）。随后，NTRK 抑制剂的批准，旨在对抗各种肿瘤类型（包括儿童癌症和成人实体瘤）中普遍存在的NTRK基因融合，进一步凸显了肿瘤不可知疗法的潜力。美国食品和药物管理局批准了靶向治疗（ BRAF V600E、 RET融合）、免疫疗法（肿瘤突变负荷≥10 个突变/兆碱基，dMMR）和抗体药物偶联物（Her2 阳性 - 免疫组织化学 3+ 表达）癌症疗效持续存在，为患有含有特定生物标志物的晚期实体瘤的患者带来了新的希望。在这篇综合综述中，作者深入研究了与组织无关的靶点和药物的广阔前景，阐明了支撑这种方法的基本原理、它面临的障碍、目前批准的疗法、来自患者倡导角度的声音以及诱人的前景地平线。这是肿瘤学领域的一项值得欢迎的进步，它超越了组织学和位置的界限，提供个性化的选择。