晚期驱动基因阳性非小细胞肺癌免疫治疗专家共识(2022版)

驱动基因阳性非小细胞肺癌既往被认为是免疫治疗"禁区", 但随着对靶向药物免疫调节作用的深入认识及临床证据的不断生成, 免疫治疗有望为驱动基因阳性非小细胞肺癌带来新希望。中国抗癌协会肿瘤精准治疗专业委员会和中华医学会杂志社肺癌研究协作组共同组织肿瘤科、呼吸科、病理科专家对驱动基因阳性人群免疫相关肿瘤及微环境特征和临床治疗的循证医学证据进行深入探讨, 并结合专家组广泛认可的临床经验, 经过共识会议制定了驱动基因阳性非小细胞肺癌免疫治疗专家共识, 旨在为中国临床医师的免疫治疗实践提供规范化指导。     

TP53共突变对驱动基因阳性肺癌靶向治疗疗效的影响及对策

非小细胞肺癌(NSCLC)的发生发展常与致癌驱动基因变异有关。虽然靶向这些驱动基因的药物取得显著疗效,但TP53共突变已被证实是肺癌靶向治疗疗效差的重要因素。针对合并TP53突变的驱动基因变异肺癌患者,联合化疗或抗血管治疗等新策略取得了重要进展。鉴于此,该文总结了TP53共突变对驱动基因阳性肺癌靶向治疗疗效的影响,以及对这部分肺癌患者最佳治疗策略的探索。     

驱动基因阳性晚期非小细胞肺癌靶向治疗

近年来,分子靶向治疗有效改善了驱动基因阳性晚期非小细胞肺癌(NSCLC)患者的预后,其中,针对存在人体表皮生长因子受体基因突变、棘皮动物微管相关样蛋白4-间变性淋巴瘤激酶融合基因、ROS1基因重排等的NSCLC患者,疗效尤为显著。对于驱动基因阳性晚期NSCLC患者,靶向治疗药物的选择尤为重要。     

TKIs治疗EML4-ALK阳性非小细胞肺癌脑转移的研究进展

摘 要：间变性淋巴瘤激酶（anaplastic lymphoma kinase,ALK）基因重排是非小细胞肺癌（NSCLC）一种新的肿瘤驱动基因,促使肺癌发生和进展。近年来针对ALK融合基因的酪氨酸激酶抑制剂崭露头角,相关药物研究在非小细胞肺癌脑转移治疗中有较大进展,成为靶向治疗的热点。全文就治疗ALK阳性NSCLC脑转移的靶向药物的临床研究作一综述。     

EML4-ALK 融合基因重排对晚期非小细胞肺癌诊断及治疗价值

肺癌的发病率和死亡率居恶性肿瘤之首,而非小细胞肺癌占所有肺癌的80%以上,研究显示EGFR及ALK是非小细胞肺癌的主要驱动基因,针对这两个靶点的靶向药物近年来取得了明显的疗效,受到了广泛关注,本文针对 EML4-ALK 融合基因重排阳性患者的相关研究进行综述。     

ALK重排非小细胞肺癌脑转移放疗的研究进展

有驱动基因突变的非小细胞肺癌脑转移较为常见,脑部放疗联合靶向药物治疗是目前研究的热点。ALK基因重排是非小细胞肺癌常见的驱动基因突变,但目前有关ALK基因重排非小细胞肺癌脑转移治疗的相关研究还较少,其预后、脑部放疗作用及放疗与ALK抑制剂有效结合值得大家探索。     

2023年CSCO指南更新解读：驱动基因阳性非小细胞肺癌诊疗

靶向治疗为驱动基因阳性的非小细胞肺癌（non-small-cell lung cancer,NSCLC）患者带来显著生存获益。伴随新药研发、临床试验的开展及阳性结果的获得,驱动基因阳性的NSCLC也迎来了更多的治疗选择、更优的疗效及安全性。中国临床肿瘤学会（Chinese Society of Clinical Oncology,CSCO）基于过去1年的研究进展更新指南为《中国临床肿瘤学会(CSCO)非小细胞肺癌诊疗指南2023》。本版针对驱动基因阳性的NSCLC的更新包括：伏美替尼和莫博赛替尼在表皮生长因子受体（epidermal growth factor receptor,EGFR）突变晚期NSCLC治疗中的相关更新,布格替尼、洛拉替尼和恩沙替尼在间变性淋巴瘤激酶（anaplastic lymphoma kinase,ALK）融合晚期NSCLC治疗中的相关更新以及其他靶向药物的更新。本文将对2023年CSCO NSCLC诊疗指南中驱动基因阳性的NSCLC的诊疗更新进行详细解读。     

非小细胞肺癌热点靶向药物及耐药机制的研究进展

非小细胞肺癌(NSCLC)已进入分子分型时代,对驱动基因及靶向用药的探索不断成熟。本文从肺癌常见驱动基因（以EGFR、ALK为主）靶向药物最新研究进展和耐药机制作以综述,以期为非小细胞肺癌患者在临床靶向用药方案选择上提供更好的参考。     

EML4-ALK融合基因与非小细胞肺癌

非小细胞肺癌是危害人类生命最常见的恶性肿瘤之一,分子靶向治疗是目前治疗非小细胞肺癌最具前景的研究领域,如何选择合适的患者一直是靶向治疗的关键.EML4-ALK融合基因是新近发现主要表达于非小细胞肺腺癌中,可能与非小细胞肺癌EGFR-TKI耐药相关的新靶点,本文就其发现过程以及研究现状进行综述.     

非小细胞肺癌伴随诊断的研究进展

非小细胞肺癌是最常见且死亡率最高的肿瘤，不同的非小细胞肺癌患者的驱动基因不同，且大多数患者通常发现晚，预后差。针对不同患者制定个性化治疗方案，选择适合的靶向药物是非小细胞肺癌的最佳治疗方案。伴随诊断通过整合多种体外诊断技术，为患者提供精确的靶向用药信息，避免患者因选择不适合的靶向药物造成不良后果。本文对非小细胞肺癌伴随诊断中的靶向生物标记物、检测技术及伴随诊断的国内外现状进行概述。     

驱动基因突变非小细胞肺癌免疫治疗的研究进展

随着肺癌靶点的发现和药物研发,靶向治疗改善了驱动基因突变非小细胞肺癌(NSCLC)的临床预后。同时,免疫检查点抑制剂在驱动基因阴性NSCLC中也取得了良好的疗效。虽然部分驱动基因突变患者从对应靶向治疗中明显获益,但对免疫治疗反应欠佳。在大部分免疫治疗临床研究和日常实践中,EGFR/ALK等驱动基因突变阳性的NSCLC患者也被排除在外,或者仅占少数。免疫治疗如何应用于驱动基因突变患者,以及如何在靶向治疗、化疗及免疫治疗中选择最佳治疗方案,制定最优治疗策略,对改善晚期驱动基因突变NSCLC患者预后至关重要。本文对不同基因突变肿瘤免疫微环境的特点及免疫治疗在不同基因突变的NSCLC患者中的应用进行简要综述。     

Successful treatment using apatinib with or without docetaxel in heavily pretreated advanced non-squamous non-small cell lung cancer: A case report and literature review

Although targeted therapy directed toward driver mutations has produced a significant efficacy benefit for patients with non-small cell lung cancer (NSCLC), many patients do not possess mutations associated with the approved targeted drugs. Angiogenic agents play an important role in the therapeutic strategy for advanced NSCLC. Apatinib is a novel tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor-2. A phase II clinical trial demonstrated the survival benefit of apatinib monotherapy in advanced NSCLC. Moreover, addition of anti-angiogenic agents to chemotherapy showed robust efficacy in advanced NSCLC, regardless of tumor histology. Here, we present the case of a heavily pretreated lung adenocarcinoma patient who was treated with apatinib and apatinib continuation plus docetaxel re-challenge. He was negative for several driver genes, including EGFR, ALK, KRAS, ROS1, HER2, RET and BRAF. The previous treatment included platinum-based doublets, pemetrexed monotherapy, docetaxel plus bevacizumab, gefitinib monotherapy, nab-paclitaxel monotherapy, irinotecan plus oxaliplatin and radiotherapy. He obtained a partial response after both apatinib monotherapy and apatinib plus docetaxel treatment, with progression-free survival durations of 5 months and 6 months, respectively. This case indicated that apatinib monotherapy or apatinib plus docetaxel might be regarded as a therapeutic option for heavily pretreated patients with advanced non-squamous NSCLC.     

Duration of Targeted Therapy in Patients With Advanced Non–small-cell Lung Cancer Identified by Circulating Tumor DNA Analysis

BackgroundOutcomes of therapy targeting molecular driver alterations detected in advanced non–small-cell lung (NSCLC) using circulating tumor DNA (ctDNA) have not been widely reported in patients who are targeted therapy-naive.Patients and MethodsWe performed a multicenter retrospective review of patients with unresectable stage IIIB to IV NSCLC who received matched therapy after a targetable driver alteration was identified using a commercial ctDNA assay through usual clinical care. Eligible patients must not have received targeted therapy prior to ctDNA testing (prior chemotherapy or immunotherapy was permitted). Kaplan-Meier analysis was used to estimate the median duration of targeted therapy. Patients still on targeted therapy were censored at last follow-up.ResultsSeventy-six patients met inclusion criteria. The median age of diagnosis of NSCLC was 64.5 years (range, 31-87 years), 67% were female, 74% were never-smokers, and 97% had adenocarcinoma histology. Twenty-one (28%) patients received systemic treatment prior to targeted therapy, including chemotherapy (n = 17), immunotherapy (n = 5), and/or a biologic (n = 4). Thirty-three (43%) patients remain on targeted therapy at the time of data analysis. The median time on targeted therapy was similar to what has been reported for tissue-detected oncogenic driver mutations in the targeted therapy-naive setting.ConclusionsPatients with ctDNA-detected drivers had durable time on targeted therapy. These treatment outcomes data compliment previous studies that have shown enhanced targetable biomarker discovery rates and high tissue concordance of ctDNA testing when incorporated at initial diagnosis of NSCLC. Identification of NSCLC driver mutations using well-validated ctDNA assays can be used for clinical decision-making and targeted therapy assignment.     

晚期肺鳞癌的治疗

肺癌是全世界肿瘤死亡的首要原因,肺鳞癌（squamous cell lung cancer, SQCLC）作为肺癌的一种常见的病理类型,全世界每年约40余万人因其致死。其常规治疗方法主要包括手术治疗、化学治疗和分子靶向治疗。但是大多数患者确诊的时候已经是晚期,失去了手术的机会。尽管分子靶向治疗在肺腺癌的治疗中具有里程碑式的作用,但是对肺鳞癌而言,尚无特异性的分子靶标药物,因此,对于晚期肺鳞癌的标准治疗仍是含铂双药方案。而大多数患者经历了一线、二线治疗失败后都面临无药可用的状态。本文旨在对晚期肺鳞癌的常规治疗进行系统性的综述,探讨晚期肺鳞癌的治疗方案以及发展方向。     

老年晚期非小细胞肺癌一线治疗

非小细胞肺癌(non-small-cell lung cancer,NSCLC)是发病率和死亡率很高的恶性肿瘤之一。随着肿瘤精准治疗快速发展,针对NSCLC的治疗手段也层出不穷。老年患者在NSCLC患者中所占比例最高,如何针对老年患者群体制定合理治疗方案非常重要。本文结合NSCLC治疗传统手段与最新进展,从驱动基因阳性和驱动基因阴性两个方面展开讨论,总结老年晚期NSCLC一线治疗的基本策略,以期为临床治疗提供参考。     

Next-generation sequencing-based identification of EGFR and NOTCH2 complementary mutations in non-small cell lung cancer

Although targeted therapy has emerged as an effective treatment strategy for non-small cell lung cancer (NSCLC), some patients cannot benefit from such therapy due to the limited number of therapeutic targets. The present study aimed to identify mutated genes associated with clinicopathological characteristics and prognosis and to screen for mutations that are not concurrent with applicable drug target sites in patients with NSCLC. Tumor tissue and blood samples were obtained from 97 patients with NSCLC. A lung cancer-specific panel of 55 genes was established and analyzed using next-generation sequencing (NGS). The results obtained from the clinical cohort were compared with the NSCLC dataset from The Cancer Genome Atlas (TCGA). Subsequently, 25 driver genes were identified by taking the intersection of the 55 lung-cancer-specific genes with three databases, namely, the Catalog of Somatic Mutations in Cancer database, the Network of Cancer Genes database and Vogelstein''s list. Functional annotation and protein-protein interaction analysis were conducted on these 25 driver genes. The χ² test and logistic regression were used to evaluate the association between mutations in the 25 driver genes and the clinicopathological characteristics of 97 patients, and phosphatase and tensin homolog (PTEN) and kirsten rat sarcoma viral oncogene homolog (KRAS) were associated with stage at diagnosis and sex, respectively, while epidermal growth factor receptor (EGFR) was associated with sex, stage at diagnosis, metastasis, CEA and CYFRA21-1. Moreover, the association between the 25 driver gene mutations and overall survival were examined using Cox regression analysis. Age and Notch homolog 2 (NOTCH2) mutations were independent prognostic factors in TCGA dataset. The correlations between statistically significant mutations in EGFR, KRAS, PTEN and NOTCH2 were further examined, both in the clinical data and TCGA dataset. There was a negative correlation between EGFR and NOTCH2 mutations (correlation coefficient, −0.078; P=0.027). Thus, the present study highlights the importance of NOTCH2 mutations and might provide novel therapeutic options for patients with NSCLC who do not harbor EGFR mutations.     

The Significance of the PD-L1 Expression in Non–Small-Cell Lung Cancer: Trenchant Double Swords as Predictive and Prognostic Markers

Lung cancer is the leading cause of death due to cancer worldwide. Surgery, chemotherapy, and radiotherapy have been the standard treatment for lung cancer, and targeted molecular therapy has greatly improved the clinical course of patients with non–small-cell lung cancer (NSCLC) harboring driver mutations, such as in epidermal growth factor receptor and anaplastic lymphoma kinase genes. Despite advances in such therapies, the prognosis of patients with NSCLC without driver oncogene mutations remains poor. Immunotherapy targeting programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) has recently been shown to improve the survival in advanced NSCLC. The PD-L1 expression on the surface of tumor cells has emerged as a potential biomarker for predicting responses to immunotherapy and prognosis after surgery in NSCLC. However, the utility of PD-L1 expression as a predictive and prognostic biomarker remains controversial because of the existence of various PD-L1 antibodies, scoring systems, and positivity cutoffs. In this review, we summarize the data from representative clinical trials of PD-1/PD-L1 immune checkpoint inhibitors in NSCLC and previous reports on the association between PD-L1 expression and clinical outcomes in patients with NSCLC. Furthermore, we discuss the future perspectives of immunotherapy and immune checkpoint factors.     

EGFR敏感突变Ⅱ~ⅢA期非小细胞肺癌治疗的研究新进展

非小细胞肺癌（non-small cell lung cancer,NSCLC）为发病率最高的恶性肿瘤,Ⅱ~ⅢA期患者为潜在可根治人群。目前,围手术期的标准治疗为化疗,而表皮生长因子受体（epidermal growth factor receptor,EGFR）敏感突变的患者,新辅助或辅助靶向治疗可提高无病生存期（disease free survival,DFS）,但是否能带来生存获益,尚未明确。ⅢA（N2）期NSCLC患者术后辅助放疗可带来生存获益,而不可手术切除的局部晚期NSCLC患者,同步放化疗后durvalumab维持治疗成为新标准。在驱动基因突变人群中的免疫治疗还有待于进一步探索,免疫治疗联合化疗可能为方向之一,而抗血管生成治疗不适宜在术后辅助治疗。      

Association between certain non–small cell lung cancer driver mutations and predictive markers for chemotherapy or programmed death‐ligand 1 inhibition

This study aimed to analyze the association between driver mutations and predictive markers for some anti–tumor agents in non–small cell lung cancer (NSCLC). A cohort of 785 Chinese patients with NSCLC who underwent resection from March 2016 to November 2017 in the First Affiliated Hospital of Guangzhou Medical University was investigated. The specimens were subjected to hybridization capture and sequence of 8 important NSCLC‐related driver genes. In addition, the slides were tested for PD‐L1, excision repair cross‐complementation group 1 (ERCC1), ribonucleotide reductase subunit M1 (RRM1), thymidylate synthase (TS) and β‐tubulin III by immunohistochemical staining. A total of 498 (63.4%) patients had at least 1 driver gene alteration. Wild‐type, EGFR rare mutation (mut), ALK fusion (fus), RAS mut, RET fus and MET mut had relatively higher proportions of lower ERCC1 expression. EGFR 19del, EGFR L858R, EGFR rare mut, ALK fus, HER2 mut, ROS1 fus and MET mut were more likely to have TS low expression. Wild‐type, EGFR L858R, EGFR rare mut and BRAF mut were associated with lower β‐tubulin III expression. In addition, wild‐type, RAS mut, ROS1 fus, BRAF and MET mut had higher proportion of PD‐L1 high expression. As a pilot validation, 21 wild‐type patients with advanced NSCLC showed better depth of response and response rate to taxanes compared with pemetrexed/gemcitabine (31.2%/60.0% vs 26.6%/45.5%). Our study may aid in selecting the optimal salvage regimen after targeted therapy failure, or the chemo‐regimen where targeted therapy has not been a routine option. Further validation is warranted.     

A pilot trial of gefitinib in combination with docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer

Despite improvements in conventional treatment, patients with advanced non-small-cell lung cancer (NSCLC) have a poor prognosis, leaving a significant unmet need for novel treatments. One such novel, biologically targeted agent is the orally active epidermal growth factor receptor tyrosine kinase inhibitor gefitinib. This open-label pilot trial investigated the safety, pharmacokinetics, and efficacy of 2 doses of gefitinib (250 and 500 mg per day) combined with docetaxel (75 mg/m2) in patients with locally advanced or metastatic NSCLC as first- and second-line chemotherapy. Eighteen patients were recruited: 6 received gefitinib 250 mg per day plus docetaxel; 12 received gefitinib 500 mg per day plus docetaxel. Combination therapy was feasible with no overlapping toxicities. No patients experienced dose-limiting toxicities (DLTs) at 250 mg per day; 1 patient had 2 DLT events at 500 mg per day (grade 3 rash and diarrhea for >4 days). Adverse events were mild to moderate, including fatigue, mucositis, nausea, anorexia, rash, diarrhea, and fever. Docetaxel did not appear to alter steady-state exposure to gefitinib. The effect of gefitinib on exposure to docetaxel was equivocal; with the exception of 2 patients in the gefitinib 250 mg per day dose group, there appeared to be no trend toward a higher or lower exposure to docetaxel when given in the presence of gefitinib compared with that when given alone. Combination therapy was associated with antitumor activity and responses were seen with gefitinib in 2 of 6 patients at 250 mg per day and 4 of 12 patients at 500 mg per day. This combination is feasible and has an acceptable and predictable safety profile, as well as associated antitumor activity.