Thein Kyaw Z, Myat Yin M, Park Byung S, Panigrahi Kalpana, Kummar Shivaani
Division of Hematology and Medical Oncology, Comprehensive Cancer Centers of Nevada-Central Valley, 3730 S Eastern Ave, Las Vegas, NV 89169, USA.
Department of Medicine, Kirk Kerkorian School of Medicine, University of Nevada Las Vegas (UNLV), 4505 S, Maryland Pkwy, Las Vegas, NV 89154, USA.
Cancers (Basel). 2024 Jul 13;16(14):2529. doi: 10.3390/cancers16142529.
The regulatory approvals of tumor-agnostic therapies have led to the re-evaluation of the drug development process. The conventional models of drug development are histology-based. On the other hand, the tumor-agnostic drug development of a new drug (or combination) focuses on targeting a common genomic biomarker in multiple cancers, regardless of histology. The basket-like clinical trials with multiple cohorts allow clinicians to evaluate pan-cancer efficacy and toxicity. There are currently eight tumor agnostic approvals granted by the Food and Drug Administration (FDA). This includes two immune checkpoint inhibitors, and five targeted therapy agents. Pembrolizumab is an anti-programmed cell death protein-1 (PD-1) antibody that was the first FDA-approved tumor-agnostic treatment for unresectable or metastatic microsatellite instability-high () or deficient mismatch repair () solid tumors in 2017. It was later approved for tumor mutational burden-high () solid tumors, although the TMB cut-off used is still debated. Subsequently, in 2021, another anti-PD-1 antibody, dostarlimab, was also approved for solid tumors in the refractory setting. Patients with fusion-positive cancers are typically difficult to treat due to their rare prevalence and distribution. Gene rearrangements or fusions are present in a variety of tumors. Neurotrophic tyrosine kinase () fusions are present in a range of pediatric and adult solid tumors in varying frequency. Larotrectinib and entrectinib were approved for neurotrophic tyrosine kinase () fusion-positive cancers. Similarly, selpercatinib was approved for rearranged during transfection () fusion-positive solid tumors. The FDA approved the first combination therapy of dabrafenib, a B-Raf proto-oncogene serine/threonine kinase (BRAF) inhibitor, plus trametinib, a mitogen-activated protein kinase (MEK) inhibitor for patients 6 months or older with unresectable or metastatic tumors (except colorectal cancer) carrying a mutation. The most recent FDA tumor-agnostic approval is of fam-trastuzumab deruxtecan-nxki (T-Dxd) for HER2-positive solid tumors. It is important to identify and expeditiously develop drugs that have the potential to provide clinical benefit across tumor types.
肿瘤非特异性疗法的监管批准促使人们重新评估药物研发过程。传统的药物研发模式是以组织学为基础的。另一方面，新型药物（或联合用药）的肿瘤非特异性药物研发专注于针对多种癌症中的一种常见基因组生物标志物，而不考虑组织学类型。包含多个队列的篮子式临床试验使临床医生能够评估泛癌疗效和毒性。美国食品药品监督管理局（FDA）目前已批准了八项肿瘤非特异性疗法。其中包括两种免疫检查点抑制剂和五种靶向治疗药物。帕博利珠单抗是一种抗程序性细胞死亡蛋白1（PD-1）抗体，它是2017年首个获FDA批准用于不可切除或转移性微卫星高度不稳定（MSI-H）或错配修复缺陷（dMMR）实体瘤的肿瘤非特异性治疗药物。后来它又被批准用于肿瘤突变负荷高（TMB-H）的实体瘤，不过所使用的TMB临界值仍存在争议。随后，在2021年，另一种抗PD-1抗体多斯塔利单抗也被批准用于难治性实体瘤。融合阳性癌症患者通常因发病率低和分布范围广而难以治疗。基因重排或融合存在于多种肿瘤中。神经营养性酪氨酸激酶（NTRK）融合在一系列儿科和成人实体瘤中以不同频率存在。拉罗替尼和恩曲替尼被批准用于神经营养性酪氨酸激酶（NTRK）融合阳性癌症。同样，塞尔帕替尼被批准用于转染重排（RET）融合阳性实体瘤。FDA批准了首个联合疗法，即用于治疗携带BRAF突变的6个月及以上不可切除或转移性肿瘤（结直肠癌除外）患者的B-Raf原癌基因丝氨酸/苏氨酸激酶（BRAF）抑制剂达拉非尼加丝裂原活化蛋白激酶（MEK）抑制剂曲美替尼。FDA最近批准的肿瘤非特异性疗法是用于HER2阳性实体瘤的fam-曲妥珠单抗德曲妥珠单抗-nxki（T-Dxd）。识别并迅速开发有可能为不同肿瘤类型带来临床益处的药物非常重要。
