Inoue Hiroyuki, Okamoto Isamu
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan.
Lung Cancer (Auckl). 2019 Dec 31;10:161-170. doi: 10.2147/LCTT.S184380. eCollection 2019.
There has been no improvement in outcome for patients with unresectable locally advanced (stage III) non-small cell lung cancer (NSCLC) for more than 10 years. The standard treatment for these patients is definitive concurrent chemotherapy and radiation (CCRT). Although the goal of treatment in this setting is to achieve a cure, most patients progress and their prognosis is poor, with a 5-year survival rate of 15-30%. There is thus an urgent need for the development of novel anticancer treatments in this patient population. Recent advances in cancer immunotherapy have led to a marked improvement in clinical outcome for advanced NSCLC. Such immunotherapy mainly consists of the administration of immune checkpoint inhibitors (ICIs) such as antibodies to cytotoxic T lymphocyte-associated protein-4 (CTLA-4) or to either programmed cell death-1 (PD-1) or its ligand PD-L1. Durvalumab (MEDI4736) is a high-affinity human immunoglobulin G1 monoclonal antibody that blocks the binding of PD-L1 on tumor cells or antigen-presenting cells to PD-1 on T cells. The PACIFIC study recently evaluated consolidation immunotherapy with durvalumab versus placebo administered after concurrent chemoradiotherapy (CCRT) in patients with unresectable stage III NSCLC. It revealed a significant improvement in both progression-free and overall survival with durvalumab, and this improvement was associated with a favorable safety profile. This achievement has made durvalumab a standard of care for consolidation after CCRT in patients with unresectable stage III NSCLC, and it has now been approved in this setting by regulatory agencies in the United States, Canada, Japan, Australia, Switzerland, Malaysia, Singapore, India, and the United Arab Emirates. In this review, we briefly summarize the results of the PACIFIC trial, including those of post hoc analysis, and we address possible molecular mechanisms, perspectives, and remaining questions related to combined treatment with CCRT and ICIs in this patient population.
10多年来，不可切除的局部晚期（III期）非小细胞肺癌（NSCLC）患者的治疗结局一直没有改善。这些患者的标准治疗是根治性同步放化疗（CCRT）。尽管这种情况下的治疗目标是治愈，但大多数患者病情进展，预后较差，5年生存率为15%-30%。因此，迫切需要为这一患者群体开发新的抗癌治疗方法。癌症免疫疗法的最新进展使晚期NSCLC的临床结局有了显著改善。这种免疫疗法主要包括给予免疫检查点抑制剂（ICI），如抗细胞毒性T淋巴细胞相关蛋白4（CTLA-4）抗体或抗程序性细胞死亡蛋白1（PD-1）或其配体PD-L1抗体。度伐利尤单抗（MEDI4736）是一种高亲和力的人免疫球蛋白G1单克隆抗体，可阻断肿瘤细胞或抗原呈递细胞上的PD-L1与T细胞上的PD-1的结合。PACIFIC研究最近评估了在不可切除的III期NSCLC患者中，同步放化疗（CCRT）后用度伐利尤单抗与安慰剂进行巩固免疫治疗的效果。结果显示，度伐利尤单抗可显著改善无进展生存期和总生存期，且这种改善与良好的安全性相关。这一成果使度伐利尤单抗成为不可切除的III期NSCLC患者CCRT后巩固治疗的标准疗法，并已在美国、加拿大、日本、澳大利亚、瑞士、马来西亚、新加坡、印度和阿联酋等国获得监管机构在这一适应症上的批准。在本综述中，我们简要总结了PACIFIC试验的结果，包括事后分析结果，并探讨了与该患者群体中CCRT和ICI联合治疗相关的可能分子机制、前景及尚存问题。
