ⅠB~ⅢA期非小细胞肺癌患者术后辅助靶向治疗研究进展

doi:10.3969/j.issn.1674-8115.2022.11.014

上海交通大学学报（医学版） ›› 2022, Vol. 42 ›› Issue (11): 1612-1619.doi: 10.3969/j.issn.1674-8115.2022.11.014

• 综述 • 上一篇

ⅠB~ⅢA期非小细胞肺癌患者术后辅助靶向治疗研究进展

李若楠(), 陈小科, 许元元, 谭强()

上海交通大学医学院附属胸科医院肿瘤科，上海 200230

收稿日期:2022-07-22 接受日期:2022-10-28 出版日期:2022-11-28 发布日期:2023-01-04
通讯作者: 谭强 E-mail:lrn0518@163.com;dr_tanqiang@sina.cn
作者简介:李若楠（1997—），女，博士生；电子信箱：lrn0518@163.com。
基金资助:
国家自然科学基金(81871497);上海交通大学“科技创新专项资金”多学科交叉项目培育(ZH2018QNA65)

Advances in postoperative adjuvant targeted therapy for patients with stage ⅠB-ⅢA non-small cell lung cancer

LI Ruonan(), CHEN Xiaoke, XU Yuanyuan, TAN Qiang()

Department of Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200230, China

Received:2022-07-22 Accepted:2022-10-28 Online:2022-11-28 Published:2023-01-04
Contact: TAN Qiang E-mail:lrn0518@163.com;dr_tanqiang@sina.cn
Supported by:
National Natural Science Foundation of China(81871497);"Science and Technology Innovation Special Fund" Multidisciplinary Cross Cultivation Project of Shanghai Jiao Tong University(ZH2018QNA65)

摘要/Abstract

摘要：

作为全球死亡率最高的癌症，肺癌的治疗一直是广大医师和患者共同面临的难题。依据分化程度、形态特征和生物学特点，肺癌可分为小细胞肺癌和非小细胞肺癌（non-small cell lung cancer，NSCLC）两大类，其中NSCLC的发生率占比80%~85%。临床上，NSCLC的常规治疗方案包括手术、化学治疗（化疗）、放射治疗、靶向药物治疗、免疫药物治疗等。对于ⅠB~ⅢA期的NSCLC患者，除首选行手术治疗外，术后还需应用辅助治疗以减少肿瘤的复发和转移。研究显示，在NSCLC的辅助治疗中靶向药物高效且安全，其中最受关注的是针对表皮生长因子受体（epidermal growth factor receptor，EGFR）基因突变的药物，即表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhibitors，EGFR-TKIs）。目前，共有3代EGFR-TKIs药物获批进入临床。其中，第一代EGFR-TKIs在辅助治疗的研究与应用中占据优势，如厄洛替尼与吉非替尼可延长术后患者的无病生存期（disease-free survival，DFS）和总生存期（overall survival，OS），埃克替尼因其可显著延长患者DFS已在中国大陆被批准用于术后辅助治疗。相较安慰剂，第三代EGFR-TKIs药物奥希替尼在ADAURA研究中展现出较为明显的DFS优势；同时，术后使用奥希替尼治疗，患者较少发生中枢神经系统复发，术后使用化疗联合奥希替尼治疗则能有更多DFS获益，因此该2种疗法成为ⅠB~ⅢA期NSCLC患者术后辅助治疗的标准方案。而阿美替尼和伏美替尼作为第三代EGFR-TKIs新药，应用于术后辅助治疗的临床试验也正在开展中。基于此，该文对EGFR的结构、EGFR基因突变类型和检测方法进行系统性总结，对临床使用EGFR-TKIs的治疗策略进行介绍，并对EGFR-TKIs在临床使用中可能遇到的问题进行探讨。

关键词: 非小细胞肺癌, 靶向治疗, 辅助治疗, 表皮生长因子受体酪氨酸激酶抑制剂, 奥希替尼

Abstract:

As the cancer with the highest mortality rate in the world, the treatment of lung cancer has always been a difficult problem for a wide range of patients and physicians alike. Based on the degree of differentiation, morphological features and biological characteristics, lung cancer can be divided into small cell lung cancer and non-small cell lung cancer (NSCLC). The incidence of NSCLC accounts for 80%?85%. Clinically, the treatment options of NSCLC include surgery, chemotherapy, radiotherapy, targeted drug therapy, immunotherapy, etc. For the patients with stage ⅠB?ⅢA NSCLC, in addition to the first choice of surgical treatment, postoperative adjuvant therapy is applied to reduce tumor recurrence and metastasis. Studies have shown that targeted drugs are efficient and safe in the adjuvant therapy for NSCLC patients, and the most attention has been given to agents that target mutations in the epidermal growth factor receptor (EGFR) gene, such as epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). At present, three generations of EGFR TKIs have been approved for clinical use. Among them, the first generation EGFR-TKIs are dominant in the research and application of adjuvant therapy. For example, erlotinib and gefitinib can prolong the disease-free survival (DFS) and overall survival (OS) of patients after surgery, and icotinib has been approved for postoperative adjuvant therapy in China because of its obvious improvement of patients' DFS. Compared with the placebo, the third generation EGFR-TKIs drug osimertinib demonstrated a more significant DFS advantage in the ADAURA trial, decreased tumor recurrence in central nervous system and brought greater benefits in DFS to patients previously treated with standard chemotherapy regime. Osimertinib or chemotherapy combined with osimertinib has therefore become the standard of care for the patients with postoperative adjuvant therapy of stage ⅠB?ⅢA NSCLC. As the third generation EGFR-TKIs new drugs, the clinical trials of almonertinib and furmonertinib for postoperative adjuvant therapy are also underway. This article systematically summarizes the structure of EGFR, the types and detection methods of EGFR gene mutations, introduces the treatment strategies of clinical use of EGFR-TKIs, and discusses the problems that may be encountered in the clinical use of EGFR-TKIs.

Key words: non-small cell lung cancer (NSCLC), targeted therapy, adjuvant therapy, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), osimertinib

中图分类号:

R655.3

李若楠, 陈小科, 许元元, 谭强. ⅠB~ⅢA期非小细胞肺癌患者术后辅助靶向治疗研究进展[J]. 上海交通大学学报（医学版）, 2022, 42(11): 1612-1619.

LI Ruonan, CHEN Xiaoke, XU Yuanyuan, TAN Qiang. Advances in postoperative adjuvant targeted therapy for patients with stage ⅠB-ⅢA non-small cell lung cancer[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(11): 1612-1619.

图/表 1

参考文献 43

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Trial	Phase	Stage	Number of enrolled patient/n	Adjuvant regimen	EGFR-TKIs duration	Primary endpoint	DFS/month	OS/month
ADJUVANT^［18-19］	Ⅲ	Ⅱ‒ⅢA （N1‒N2）（7^th TNM）	222	Adjuvant gefitinib vs VP	2 years	Median DFS	30.8 vs 19.8， HR （95%CI）=0.51 （0.36‒0.72）	75.5 vs 62.8， HR （95%CI）=0.92 （0.62‒1.36）
IMPACT^［20］	Ⅲ	Ⅱ‒ⅢA （N1‒N2）（7^th TNM）	234	Adjuvant gefitinib vs VP	2 years	Median DFS	35.9 vs 25.0， HR （95%CI）=0.92 （0.67‒1.28）	NR vs NR， HR （95%CI）=1.03 （0.65‒1.65）
EVIDENCE^［21］	Ⅲ	Ⅱ‒ⅢA （7^th TNM）	322	Adjuvant icotinib vs VP or cis/pem	2 years	Median DFS	47.0 vs 22.1， HR （95%CI）=0.36 （0.24‒0.55）	NR vs NR， HR （95%CI）=0.91 （0.42‒1.94）
ADAURA^［22］	Ⅲ	ⅠB‒ⅢA （N1‒N2）（7^th TNM）	682	Adjuvant chemotherapy （optional） followed by osimertinib vs adjuvant chemotherapy followed by placebo	3 years	Median DFS Ⅱ‒ⅢA	NR vs 20.4， HR （95%CI）=0.17 （0.11‒0.26）	NR vs NR， HR （95%CI）=0.40 （0.18‒0.90）

Trial	Phase	Stage	Number of enrolled patient/n	Adjuvant regimen	EGFR-TKIs duration	Primary endpoint	DFS/month	OS/month
ADJUVANT^［18-19］	Ⅲ	Ⅱ‒ⅢA （N1‒N2）（7^th TNM）	222	Adjuvant gefitinib vs VP	2 years	Median DFS	30.8 vs 19.8， HR （95%CI）=0.51 （0.36‒0.72）	75.5 vs 62.8， HR （95%CI）=0.92 （0.62‒1.36）
IMPACT^［20］	Ⅲ	Ⅱ‒ⅢA （N1‒N2）（7^th TNM）	234	Adjuvant gefitinib vs VP	2 years	Median DFS	35.9 vs 25.0， HR （95%CI）=0.92 （0.67‒1.28）	NR vs NR， HR （95%CI）=1.03 （0.65‒1.65）
EVIDENCE^［21］	Ⅲ	Ⅱ‒ⅢA （7^th TNM）	322	Adjuvant icotinib vs VP or cis/pem	2 years	Median DFS	47.0 vs 22.1， HR （95%CI）=0.36 （0.24‒0.55）	NR vs NR， HR （95%CI）=0.91 （0.42‒1.94）
ADAURA^［22］	Ⅲ	ⅠB‒ⅢA （N1‒N2）（7^th TNM）	682	Adjuvant chemotherapy （optional） followed by osimertinib vs adjuvant chemotherapy followed by placebo	3 years	Median DFS Ⅱ‒ⅢA	NR vs 20.4， HR （95%CI）=0.17 （0.11‒0.26）	NR vs NR， HR （95%CI）=0.40 （0.18‒0.90）

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ⅠB~ⅢA期非小细胞肺癌患者术后辅助靶向治疗研究进展

Advances in postoperative adjuvant targeted therapy for patients with stage ⅠB-ⅢA non-small cell lung cancer

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