Liu Iris H, Kunz Pamela L
Stanford University School of Medicine, Stanford, CA, USA.
J Gastrointest Oncol. 2017 Jun;8(3):457-465. doi: 10.21037/jgo.2016.12.09.
The development of biologic agents has ushered in a new era of precision medicine, opening the door to new therapeutic options designed to intelligently target cancer cells and their promoting factors, while leaving normal cells relatively unharmed. Biologics for the treatment of neuroendocrine tumors (NETs) have followed in the footsteps of regimens targeting pathways upregulated in other cancers, including the vascular endothelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR). Through a number of clinical trials, the mTOR inhibitor everolimus and the receptor tyrosine kinase (RTK) inhibitor sunitinib were recently approved for NETs. Other biologics such as the VEGF-A inhibitor bevacizumab have also demonstrated promising clinical activity in NETs. Interestingly, though trials have demonstrated the efficacy of everolimus and sunitinib in extending progression-free survival (PFS) in NETs, objective response rates (RR) are uniformly low, indicating that the primary effect of these drugs is maintenance of stable disease. Due to the relatively indolent nature of the more common, well-differentiated variety of NETs, stable disease is often a reasonable goal for NET patients. Well-differentiated NETs have been shown to be poor responders to cytotoxic chemotherapy, underlining the important role of biologics in treating and managing NETs and their hormonal symptoms. Ongoing and future trials are investigating a wide variety of biologic compounds in NETs, including other RTK inhibitors, mTOR pathway inhibitors, and immune checkpoint inhibitors. Within this review, we will discuss major trials leading up to the FDA approval of everolimus and sunitinib for NETs, as well as other promising biologics currently under investigation in NET clinical trials.
生物制剂的发展开创了精准医学的新时代，为旨在智能靶向癌细胞及其促进因子的新治疗选择打开了大门，同时使正常细胞相对免受伤害。用于治疗神经内分泌肿瘤（NETs）的生物制剂遵循了针对其他癌症中上调通路的治疗方案的脚步，包括血管内皮生长因子（VEGF）和雷帕霉素靶蛋白（mTOR）。通过多项临床试验，mTOR抑制剂依维莫司和受体酪氨酸激酶（RTK）抑制剂舒尼替尼最近被批准用于NETs。其他生物制剂，如VEGF-A抑制剂贝伐单抗，在NETs中也显示出有前景的临床活性。有趣的是，尽管试验已证明依维莫司和舒尼替尼在延长NETs的无进展生存期（PFS）方面有效，但客观缓解率（RR）一直很低，这表明这些药物的主要作用是维持疾病稳定。由于更常见的、分化良好的NETs性质相对惰性，疾病稳定通常是NET患者的一个合理目标。已证明分化良好的NETs对细胞毒性化疗反应不佳，这突出了生物制剂在治疗和管理NETs及其激素症状方面的重要作用。正在进行和未来的试验正在研究NETs中的多种生物化合物，包括其他RTK抑制剂、mTOR通路抑制剂和免疫检查点抑制剂。在这篇综述中，我们将讨论FDA批准依维莫司和舒尼替尼用于NETs之前的主要试验，以及目前正在NET临床试验中研究的其他有前景的生物制剂。
