Medical Oncology, Careggi University Hospital, Florence, Italy.
Department of Health Sciences, University of Florence, Florence, Italy.
Clin Drug Investig. 2020 Jun;40(6):519-527. doi: 10.1007/s40261-020-00915-5.
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.
在精准肿瘤学的不断发展中，对肿瘤的基因组特征进行分析已变得至关重要，因为这有助于针对绝大多数癌症开展基于分子的治疗。最近，由于鉴定出新型致癌靶点和开发出新的靶向疗法，以及随后对基因组测序的最新应用，转化研究为系统癌症治疗提供了新的视角。与此同时，下一代测序（NGS）的应用范围不断扩大，在初始筛选、疾病进展时，甚至在分子变化的纵向监测中，都已将其纳入临床研究。因此，在几种不同类型的肿瘤中发现了新的潜在可靶向的分子改变，从而开发出了针对肿瘤的治疗方法。这些药物对特定的分子改变具有高度选择性，对不同亚型的致癌基因依赖性癌症有效。其中三种药物——帕博利珠单抗（一种抗程序性死亡受体 1（PD-1）单克隆抗体（mAb））、拉罗替尼（一种泛原肌球蛋白受体酪氨酸激酶（TRK）抑制剂）和恩曲替尼（一种泛 TRK、间变性淋巴瘤激酶（ALK）和 ROS-1 抑制剂）——分别于 2017 年、2018 年和 2019 年获得美国食品和药物管理局（FDA）批准。本文我们批判性地回顾了这些获得 FDA 批准的临床研究，并讨论了最新的更新结果。然后，我们讨论了这些新方法学方法的优势和局限性，特别关注最大的精准医学主方案 NCI-MATCH。这些优势包括增加了为具有不同类型肿瘤中鉴定出的特定改变的患者提供靶向治疗的机会。其中的局限性包括，相同的驱动突变可能需要不同的治疗策略，而在不同类型的癌症中。此外，不可否认，复杂的研究设计需要一种动态策略来招募具有相当经济和管理努力的患者。
