Department of Pharmacotherapy and Translational Research, University of Florida, Jacksonville, Florida, USA.
Center for Pharmacogenomics and Translational Research, Nemours Children's Specialty Care, Jacksonville, Florida, USA.
Clin Pharmacol Ther. 2021 Feb;109(2):334-342. doi: 10.1002/cpt.1946. Epub 2020 Jul 16.
Targeted therapies have reshaped the landscape of the development of cancer therapeutics. Recent biomarker-driven, tissue-agnostic clinical trials represent a significant paradigm shift in precision cancer medicine. Despite their growth in preclinical and clinical studies, to date only a few biomarker-driven, tissue-agnostic indications have seen approval by the US Food and Drug Administration (FDA). These approvals include pembrolizumab in microsatellite instability-high or mismatch repair deficient solid tumors, as well as both larotrectinib and entrectinib in NTRK fusion-positive tumors. Complex cancer biology, clinical trial design, and identification of resistance mechanisms represent some of the challenges that future tissue-agnostic therapies have to overcome. In this Review, we present a brief history of the development of tissue-agnostic therapies, comparing the similarities in the approval of pembrolizumab, larotrectinib, and entrectinib for tissue-agnostic indications. We also explore the future of tissue-agnostic cancer therapeutics while identifying important challenges for the future that drugs targeting tissue-agnostic indications will face.
靶向治疗已经改变了癌症治疗药物开发的格局。最近基于生物标志物的、组织不可知的临床试验代表了精准癌症医学的重大范式转变。尽管在临床前和临床试验中得到了广泛研究，但迄今为止，只有少数基于生物标志物的、组织不可知的适应症获得了美国食品和药物管理局 (FDA) 的批准。这些批准包括 pembrolizumab 在微卫星不稳定高或错配修复缺陷的实体瘤中的应用，以及 larotrectinib 和 entrectinib 在 NTRK 融合阳性肿瘤中的应用。复杂的癌症生物学、临床试验设计和耐药机制的鉴定是未来组织不可知治疗方法需要克服的一些挑战。在这篇综述中，我们简要介绍了组织不可知治疗方法的发展历史，比较了 pembrolizumab、larotrectinib 和 entrectinib 获得组织不可知适应症批准的相似之处。我们还探讨了组织不可知癌症治疗的未来，同时确定了靶向组织不可知适应症的药物未来将面临的重要挑战。
