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Tumor-Agnostic Treatment for Cancer: When How is Better than Where

机译：癌症患者治疗：何时比哪里好

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摘要

In the evolving landscape of precision oncology, genomic characterization of tumor has become crucial in order to move toward a molecular-based therapy for the vast majority of cancers. Recently, translational research has offered new perspectives in systemic cancer treatment thanks to the identification of novel oncogenic targets and the development of new targeted therapies, followed by the latest applications of genomic sequencing. Simultaneously, next-generation sequencing (NGS) has expanded its accessibility, being incorporated into clinical studies at the time of the initial screening, disease progression, and often in longitudinal monitoring of molecular changes. Consequently, new potentially targetable molecular alterations have been identified in several different types of tumors, leading to the development of tumor-agnostic treatments. Being highly selective for specific molecular alterations, these drugs are active against different subtypes of oncogene-addicted cancers. Three of these drugs-pembrolizumab [an anti-programmed death 1 (PD-1) monoclonal antibody (MAb)], larotrectinib [a pan-tropomyosin receptor tyrosine kinase (TRK) inhibitor], and entrectinib [a pan-TRK, anaplastic lymphoma kinase (ALK) and ROS-1 inhibitor]-received US FDA approval in 2017, 2018, and 2019, respectively. In this article, we critically review the clinical studies responsible for FDA approval and the most recently updated results. We then discuss the benefits and limitations of these new methodological approaches, paying particular attention to the largest precision medicine master protocol, NCI-MATCH. Among the benefits, there are the increased chances of offering targeted therapies for patients with specific alterations identified in different types of tumors. Among the limitations, we highlight that the same driver mutation may require different therapeutic strategies in different types of cancers. Additionally, the complex study design undeniably requires a dynamic strategy to enroll patients with considerable economic and managerial efforts.
机译：在精密肿瘤的不断发展景观中，肿瘤的基因组表征是至关重要的，以便朝着绝大多数癌症的分子治疗。最近，由于新型致癌目标和新的靶向疗法的发展，翻译研究提供了全身癌症治疗的新观点，其次是基因组测序的最新应用。同时，下一代测序（NGS）扩展了其可访问性，并在初始筛查，疾病进展的时间内纳入临床研究，通常在分子变化的纵向监测中。因此，已经在几种不同类型的肿瘤中鉴定出新的潜在靶向分子改变，导致肿瘤无症状治疗的发展。对于特定的分子改变是高度选择性的，这些药物对癌基因上瘾的癌症的不同亚型有效。其中三种药物-pembrolizumab [抗程序死亡1（pd-1）单克隆抗体（mAb）]，Larotrectinib [泛 - 冠状阴性素受体酪氨酸激酶（Trk）抑制剂]和entectinib [泛动脉胸腺淋巴瘤激酶（ALK）和ROS-1抑制剂] - 2017年，2018年和2019年的美国FDA批准分别。在本文中，我们重视负责FDA批准的临床研究以及最近更新的结果。然后，我们讨论了这些新方法方法的益处和局限，特别注意了最大的精密医学硕士协议，NCI匹配。在这些益处中，为在不同类型的肿瘤中鉴定的患者提供针对性疗法的增加的机会。在限制中，我们强调了相同的驾驶员突变可能需要不同类型的癌症的不同治疗策略。此外，复杂的研究设计无可否认需要一种充满活力的策略，以招收具有相当经济和管理努力的患者。

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