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 (MSI-H) or deficient mismatch repair (dMMR) solid tumors in 2017. It was later approved for tumor mutational burden-high (TMB-H) solid tumors, although the TMB cut-off used is still debated. Subsequently, in 2021, another anti-PD-1 antibody, dostarlimab, was also approved fordMMRsolid 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 (NTRK) fusions are present in a range of pediatric and adult solid tumors in varying frequency. Larotrectinib and entrectinib were approved for neurotrophic tyrosine kinase (NTRK) fusion-positive cancers. Similarly, selpercatinib was approved for rearranged during transfection (RET) 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 aBRAFV600Emutation. 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.
肿瘤未知型疗法的监管批准促使药物研发流程被重新评估。传统的药物研发模式基于组织学分型。而肿瘤未知型新药（或联合疗法）的开发则聚焦于针对多种癌症中共同的基因组生物标志物，无论其组织学类型如何。采用多队列篮子式临床试验使临床医生能够评估泛癌种的疗效和毒性。目前美国食品药品监督管理局（FDA）已批准了八种肿瘤未知型疗法。其中包括两种免疫检查点抑制剂和五种靶向治疗药物。派姆单抗是一种抗程序性细胞死亡蛋白-1（PD-1）抗体，于2017年成为首个获得FDA批准的肿瘤未知型疗法，用于治疗不可切除或转移性微卫星不稳定性高（MSI-H）或错配修复缺陷（dMMR）的实体瘤。随后，该药又获批用于肿瘤突变负荷高（TMB-H）的实体瘤，尽管所使用的TMB阈值仍存在争议。接着在2021年，另一种抗PD-1抗体多塔利单抗也获批用于难治性dMMR实体瘤。融合阳性癌症患者因其罕见性和分布特点通常难以治疗。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）融合在一系列儿童和成人实体瘤中以不同频率存在。拉罗替尼和恩曲替尼获批用于治疗NTRK融合阳性癌症。类似地，塞尔帕替尼获批用于转染重排（RET）融合阳性实体瘤。FDA批准了首个联合疗法——达拉非尼（一种B-Raf原癌基因丝氨酸/苏氨酸激酶（BRAF）抑制剂）联合曲美替尼（一种丝裂原活化蛋白激酶（MEK）抑制剂），用于治疗6个月及以上、携带BRAF V600E突变、不可切除或转移性（结直肠癌除外）肿瘤患者。FDA最近批准的肿瘤未知型疗法是fam-曲妥珠单抗德鲁替康-nxki（T-Dxd），用于治疗HER2阳性实体瘤。识别并加速开发具有跨肿瘤类型提供临床获益潜力的药物至关重要。
Target-Driven Tissue-Agnostic Drug Approvals—A New Path of Drug Development
肿瘤(癌症)患者之家