Osimertinib in patients with epidermal growth factor receptor T790M advanced non‐small cell lung cancer selected using cytology samples

Osimertinib is a potent, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for EGFR‑TKI sensitizing (EGFRm) and T790M resistance mutations. The primary objective of the cytology cohort in the AURA study was to investigate safety and efficacy of osimertinib in pretreated Japanese patients with EGFR T790M mutation‐positive non‐small cell lung cancer (NSCLC), with screening EGFR T790M mutation status determined from cytology samples. The cytology cohort was included in the Phase I dose expansion component of the AURA study. Patients were enrolled based on a positive result of T790M by using cytology samples, and received osimertinib 80 mg in tablet form once daily until disease progression or until clinical benefit was no longer observed at the discretion of the investigator. Primary endpoint for efficacy was objective response rate (ORR) by investigator assessment. Twenty‐eight Japanese patients were enrolled into the cytology cohort. At data cut‐off (February 1, 2016), 12 (43%) were on treatment. Investigator‐assessed ORR was 75% (95% confidence interval [CI] 55, 89) and median duration of response was 9.7 months (95% CI 3.8, not calculable [NC]). Median progression‐free survival was 8.3 months (95% CI 4.2, NC) and disease control rate was 96% (95% CI 82, 100). The most common all‐causality adverse events were paronychia (46%), dry skin (46%), diarrhea (36%) and rash (36%). Osimertinib provided clinical benefit with a manageable safety profile in patients with pretreated EGFR T790M mutation‐positive NSCLC whose screening EGFR T790M mutation‐positive status was determined from cytology samples. (ClinicalTrials.gov number NCT01802632).     

Amphiregulin triggered epidermal growth factor receptor activation confers in vivo crizotinib‐resistance of EML4‐ALK lung cancer and circumvention by epidermal growth factor receptor inhibitors

Crizotinib, a first‐generation anaplastic lymphoma kinase (ALK) tyrosine‐kinase inhibitor, is known to be effective against echinoderm microtubule‐associated protein‐like 4 (EML4)‐ALK‐positive non‐small cell lung cancers. Nonetheless, the tumors subsequently become resistant to crizotinib and recur in almost every case. The mechanism of the acquired resistance needs to be deciphered. In this study, we established crizotinib‐resistant cells (A925LPE3‐CR) via long‐term administration of crizotinib to a mouse model of pleural carcinomatous effusions; this model involved implantation of the A925LPE3 cell line, which harbors the EML4‐ALK gene rearrangement. The resistant cells did not have the secondary ALK mutations frequently occurring in crizotinib‐resistant cells, and these cells were cross‐resistant to alectinib and ceritinib as well. In cell clone #2, which is one of the clones of A925LPE3‐CR, crizotinib sensitivity was restored via the inhibition of epidermal growth factor receptor (EGFR) by means of an EGFR tyrosine‐kinase inhibitor (erlotinib) or an anti‐EGFR antibody (cetuximab) in vitro and in the murine xenograft model. Cell clone #2 did not have an EGFR mutation, but the expression of amphiregulin (AREG), one of EGFR ligands, was significantly increased. A knockdown of AREG with small interfering RNAs restored the sensitivity to crizotinib. These data suggest that overexpression of EGFR ligands such as AREG can cause resistance to crizotinib, and that inhibition of EGFR signaling may be a promising strategy to overcome crizotinib resistance in EML4‐ALK lung cancer.     

表皮生长因子受体突变:gefitinib和erlotinib治疗非小细胞肺癌的靶点研究进展

Gefitinib和erlotinib是表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)类药物,是目前治疗非小细胞肺癌(NSCLC)的热点,已在多个临床试验中证实,东亚人群、女性、无吸烟史和腺癌患者有效,进一步的研究揭示癌症病人EGFR酪氨酸激酶区突变与对EGFR-TKI的敏感性密切相关。这些突变包括框架缺失、点突变等多种类型。本文综述了EGFR突变的研究现状和进展。     

Detection of epidermal growth factor receptor mutations in plasma by mutant‐enriched PCR assay for prediction of the response to gefitinib in patients with non‐small‐cell lung cancer

The high frequency of epidermal growth factor receptor (EGFR) mutations in tyrosine kinase inhibitor‐responsive non‐small‐cell lung cancer (NSCLC) cases is now well established, highlighting the predictive value of activating EGFR mutations in guiding the clinical use of EGFR‐targeted therapies. However, specimen source and methods for EGFR mutation analysis are limited by tissue availability and technical feasibility in clinical application. Therefore, the current study is designed to establish a blood‐based approach for the assessment of EGFR mutations in NSCLC patients, in particular the advanced stage, and to test its clinical application. Plasma samples were obtained from the enrolled 134 NSCLC patients. The detection rate of the EGFR exon19 deletions and exon21 L858R was 49.3% (66/134) by the blood‐based, mutant‐enriched polymerase chain reaction. In the paired tumor and plasma samples, the detected mutant types of each pair respectively by direct sequencing and mutant‐enriched polymerase chain reaction were concordant in 17 of 18 (94.4%). In the patients treated with gefitinib as a second‐line therapy, those with plasma EGFR mutation have a prolonged median progression‐free survival compared with those with EGFR wild type (7.609 vs. 2.877 months, p = 0.002). On comparing the efficacy of gefitinib with that of docetaxel, it was found that the median progression‐free survival was significantly longer for patients treated with gefitinib than those with docetaxel in those harboring plasma EGFR mutation (7.609 vs. 3.192 months, p = 0.006). These results suggest that the blood‐based EGFR mutations test has the ability to provide a reliable guidance for clinical decision making for the treatment of the advanced NSCLC patients. © 2009 UICC     

Targeting epidermal growth factor receptor in lung cancer: Perspective from the Asia–Pacific region

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase of the ErbB family that is frequently overexpressed in non‐small cell lung cancer (NSCLC), and has been identified as a novel therapeutic target for lung cancer. The development of small molecule EGFR‐tyrosine kinase inhibitors (TKI) such as gefitinib and erlotinib has resulted in paradigm shift in the treatment of advanced NSCLC. The impact of EGFR‐TKI in the treatment of NSCLC is even greater in Asia–Pacific region because one of the greatest clinical benefits of EGFR‐TKI has been seen in patients of East Asian ethnicity. The discovery of somatic mutations in EGFR‐tyrosine kinase domain has so far answered some, but not all, of the questions regarding the clinical response to EGFR‐TKI in NSCLC. In addition, other molecular profiles such as KRAS mutations have also been found to play an important role in EGFR targeted therapy. In this article, we review EGFR targeted therapy in NSCLC with the focus on perspective from the Asia–Pacific region.     

Rebiopsy for patients with non‐small‐cell lung cancer after epidermal growth factor receptor‐tyrosine kinase inhibitor failure

Although third‐generation epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKI) can overcome T790M‐mediated resistance in non‐small‐cell lung cancer (NSCLC), rebiopsy to confirm T790M status is occasionally difficult. We aimed to investigate the current tendency and the limitations of rebiopsy in clinical practice. This study included 139 consecutive NSCLC patients with EGFR mutations, who had experienced progressive disease (PD) after EGFR‐TKI treatment. We retrospectively reviewed patient characteristics, tumor progression sites and rebiopsy procedures. Of 120 patients (out of the original 139) who were eligible for clinical trials, 75 (63%) underwent rebiopsy for 30 pleural effusions, 32 thoracic lesions, four bone, two liver, and seven at other sites. Rebiopsy procedures included 30 thoracocentesis, 24 transbronchial biopsies, 13 computed tomography (CT)‐guided needle biopsies and 8 other procedures. Of the 75 rebiopsied patients, 71 (95%) were pathologically diagnosed with malignancy; and 34 (45%) had available tissue samples for EGFR analyses. Of the 75 biopsied patients, 61 (81%) were analyzed for EGFR mutation, using tissue or cytology samples; T790M mutations were identified in 20 (33%) of the 61 patients. Of the 120 patients, 45 (38%) did not undergo rebiopsy, because of inaccessible tumor sites (n = 19), patient refusal (n = 6) or decision of physician (n = 10). In conclusion, among patients with EGFR mutations who had PD after EGFR‐TKI treatment, 63% underwent rebiopsy. Most rebiopsy samples were diagnosed with malignancy. However, tissue samples were less available and T790M mutations were identified less frequently than in previous studies. Skill and experience with rebiopsy and noninvasive alternative methods will be increasingly important.     

Osimertinib in Japanese patients with EGFR T790M mutation‐positive advanced non‐small‐cell lung cancer: AURA3 trial

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the first‐line treatment for patients with EGFR mutant non‐small‐cell lung cancer (NSCLC). However, most patients become resistant to these drugs, so their disease progresses. Osimertinib, a third‐generation EGFR‐TKI that can inhibit the kinase even when the common resistance‐conferring Thr790Met (T790M) mutation is present, is a promising therapeutic option for patients whose disease has progressed after first‐line EGFR‐TKI treatment. AURA3 was a randomized (2:1), open‐label, phase III study comparing the efficacy of osimertinib (80 mg/d) with platinum‐based therapy plus pemetrexed (500 mg/m²) in 419 patients with advanced NSCLC with the EGFR T790M mutation in whom disease had progressed after first‐line EGFR‐TKI treatment. This subanalysis evaluated the safety and efficacy of osimertinib specifically in 63 Japanese patients enrolled in AURA3. The primary end‐point was progression‐free survival (PFS) based on investigator assessment. Improvement in PFS was clinically meaningful in the osimertinib group (n = 41) vs the platinum‐pemetrexed group (n = 22; hazard ratio 0.27; 95% confidence interval, 0.13‐0.56). The median PFS was 12.5 and 4.3 months in the osimertinib and platinum‐pemetrexed groups, respectively. Grade ≥3 adverse events determined to be related to treatment occurred in 5 patients (12.2%) treated with osimertinib and 12 patients (54.5%) treated with platinum‐pemetrexed. The safety and efficacy results in this subanalysis are consistent with the results of the overall AURA3 study, and support the use of osimertinib in Japanese patients with EGFR T790M mutation‐positive NSCLC whose disease has progressed following first‐line EGFR‐TKI treatment. (ClinicalTrials.gov trial registration no. NCT02151981.)     

A multiparametric study on the prognostic value of epidermal growth factor receptor in operable breast carcinoma

Summary Epidermal growth factor receptor (EGFR) is a potentially useful new biological prognostic and predictive indicator in human breast cancer. Additional research on EGFR is warranted to enhance our information on: i) the method of choice for its detection and quality control issues; ii) its association with novel pathobiological markers of prognosis; iii) its prognostic value in multivariate analysis; and iv) its capability to predict response to hormone therapy and, in the future, to biological treatments using antibodies against the specific receptor or its ligands.In the present study we update previous data on EGFR status, determined immunocytochemically, by prolonging the period of observation up to 5 years and by including, in the multivariate analysis, several new biological indicators. The main results obtained are: i) EGFR is weakly associated with Ki-67 score (p=0.073) and with p53 expression (p=0.06); ii) EGFR is a significant indicator for recurrence (p<0.01 and odds ratio of 2.82) but not for death (p=0.27 and odds ratio of 1.49); iii) the prognostic power of EGFR is enhanced when combined with the knowledge of S-phase fraction; and iv) in multivariate analysis on relapse-free survival, EGFR and S-phase fraction (likelihood ratio test=26.40; p<0.01), c-erbB-2 protein and p53 mutant protein expression (likelihood ratio test= 5.94; p=0.05), cathepsin D (likelihood ratio test= 9.78; p<0.01), and nodal status (likelihood ratio test= 7.32; p<0.01) are significant and independent prognostic factors in early-stage breast carcinoma.This new information could be of help for a more rational approach in the use of EGFR as a marker in future clinical research.     

Preclinical antitumor activity of S‐222611, an oral reversible tyrosine kinase inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2

Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) are validated molecular targets in cancer therapy. Dual blockade has been explored and one such agent, lapatinib, is in clinical practice but with modest activity. Through chemical screening, we discovered a novel EGFR and HER2 inhibitor, S‐222611, that selectively inhibited both kinases with IC₅₀s below 10 nmol/L. S‐222611 also inhibited intracellular kinase activity and the growth of EGFR‐expressing and HER2‐expressing cancer cells. In addition, S‐222611 showed potent antitumor activity over lapatinib in a variety of xenograft models. In evaluations with two patient‐oriented models, the intrafemoral implantation model and the intracranial implantation model, S‐222611 exhibited excellent activity and could be effective against bone and brain metastasis. Compared to neratinib and afatinib, irreversible EGFR/HER2 inhibitors, S‐222611 showed equivalent or slightly weaker antitumor activity but a safer profile. These results indicated that S‐222611 is a potent EGFR and HER2 inhibitor with substantially better antitumor activity than lapatinib at clinically relevant doses. Considering the safer profile than for irreversible inhibitors, S‐222611 could be an important option in future cancer therapy.     

Sensitivity of epidermal growth factor receptor and ErbB2 exon 20 insertion mutants to Hsp90 inhibition

The mature epidermal growth factor receptor (EGFR) neither associates with nor requires the molecular chaperone heat-shock protein 90 (Hsp90). Mutations in EGFR exons 18, 19, and 21 confer Hsp90 chaperone dependence. In non-small cell lung cancer (NSCLC), these mutations are associated with enhanced sensitivity to EGFR inhibitors in vitro and with clinical response in vivo. Although less prevalent, insertions in EGFR exon 20 have also been described in NSCLC. These mutations, however, confer resistance to EGFR inhibitors. In NSCLC, exon 20 insertions have also been identified in the EGFR family member ErbB2. Here, we examined the sensitivity of exon 20 insertion mutants to an Hsp90 inhibitor currently in the clinic. Our data demonstrate that both EGFR and ErbB2 exon 20 insertion mutants retain dependence on Hsp90 for stability and downstream-signalling capability, and remain highly sensitive to Hsp90 inhibition. Use of Hsp90 inhibitors should be considered in NSCLC harbouring exon 20 insertions in either EGFR or ErbB2.     

表皮生长因子、雄激素受体和表皮生长因子受体在肝癌组织中的表达及影响因素分析

目的探讨肝癌患者肝癌组织中的表皮生长因子(EGF)、雄激素受体(AR)、表皮生长因子受体(EGFR)的表达情况及临床意义。方法采用免疫组织化学染色法检测EGF、AR、EGFR在90例肝癌患者的肝癌组织和90例非肝癌患者的非肝癌组织中的表达情况,比较不同临床特征肝癌患者肝癌组织中EGF、AR、EGFR的表达情况,分析肝癌患者肝癌组织中EGF、AR、EGFR表达的影响因素。结果肝癌组织中的EGF、AR、EGFR的阳性表达率均明显高于非肝癌组织,差异均有统计学意义(P﹤0.01)。有肝炎史、Ⅲ+Ⅳ期、中低分化、有淋巴结转移的肝癌患者肝癌组织中EGF、AR、EGFR的阳性表达率均高于无肝炎史、Ⅰ+Ⅱ期、高分化、无淋巴结转移的肝癌患者,差异均有统计学意义(P﹤0.05);不同年龄、性别、肿瘤直径的肝癌患者肝癌组织中EGF、AR、EGFR的阳性表达率比较,差异均无统计学意义(P﹥0.05)。Logistic回归分析结果显示,有淋巴结转移、TNM分期为Ⅲ+Ⅳ期是肝癌患者肝癌组织中EGF、AR、EGFR表达的独立危险因素。结论EGF、AR、EGFR在肝癌患者的肝癌组织中呈高表达,且其表达与肝癌患者的淋巴结转移情况和TNM分期密切相关。     

Management of acquired resistance to epidermal growth factor receptor kinase inhibitors in patients with advanced non‐small cell lung cancer

The widespread adoption of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors for the first‐line treatment of patients with advanced EGFR‐mutated non‐small cell lung cancer has resulted in acquired tyrosine kinase inhibitor resistance becoming a ubiquitous clinical problem. The identification of specific mechanisms of acquired resistance has allowed a better understanding of the biology and natural history of resistant disease, but is only now starting to impact treatment decisions. Strategies for managing acquired resistance in patients with advanced non‐small cell lung cancer are complex and must be adapted to the individual characteristics of each patient's cancer. Although combination chemotherapy is the presumed standard of care for most patients, prospective trial data are lacking, highlighting the importance of offering patients participation in clinical trials in this setting. Emerging data from trials of third‐generation mutant‐specific EGFR kinase inhibitors suggests particular promise with this class of agents. Cancer 2014;120:2289–2298. © 2014 American Cancer Society.     

非小细胞肺癌中表皮生长因子受体基因突变ADx-ARMS分析及其与临床病理特征的相关性

目的:回顾性分析非小细胞肺癌(NSCLC)中采用ADx-ARMS法检测的表皮生长因子受体(EGFR)的基因突变率、突变分布特征及其与临床病理特征的相关性。方法:收集NSCLC标本共139例,其中包括手术切除样本 83 例、穿刺活检样本27 例、胸腔积液样本 18例及血液样本11例。所有样本均采用ADx-ARMS法检测EGFR基因酪氨酸激酶编码区第19至21号外显子的突变。 结果:在139例NSCLC标本中共检测出EGFR基因突变53例,突变率为38.1%;第19至21号外显子的突变率分别为43.4%(23/53)、0(0/53) 和56.6%(30/53);年龄大于等于中位年龄(60岁)与小于中位年龄的患者EGFR基因突变率分别为35.6%(26/73) 和40.9%(27/66),差异无统计学意义(P>0.05);女性患者中EGFR基因突变率(49.0%,25/51) 高于男性患者基因突变率(31.8%,28/88,P<0.05);腺癌中的基因突变率(41.8%,46/110)显著高于鳞癌(15.0%,3/20,P<0.01),而与未能分型的患者(37.5%,3/8)差异无统计学意义(P>0.05)。在手术切除、穿刺活检、胸腔积液以及血液样本中EGFR基因突变检出率分别为42.2%(35/83)、37.0%(10/27)、38.9%(7/18)和9.1%(1/11)。 结论:ADx-ARMS法是检测NSCLC中EGFR基因突变的快速有效方法,但不能检测未知突变类型。EGFR基因的总突变率与年龄无显著相关性;EGFR基因突变在女性和腺癌中多见;EGFR基因突变检出率与样本类型密切相关,对无法取得切除样本的患者,穿刺活检及胸腔积液样本是检测EGFR基因突变的有效样本。     

Activity of a specific inhibitor, gefitinib (Iressa, ZD1839), of epidermal growth factor receptor in refractory non-small-cell lung cancer.

BACKGROUND: Gefitinib (Iressa(TM), ZD1839) is an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. Phase I studies showed that it is well tolerated, with evidence of tumor regression in patients with advanced non-small-cell lung cancer (NSCLC). Therefore, we aimed to assess the antitumor activity and tolerability of gefitinib in a series of patients with previously treated, advanced NSCLC, as a part of a compassionate use program. PATIENTS AND METHODS: To be eligible, all patients were required to have histologically or cytologically proven advanced or metastatic NSCLC, prior chemotherapy with at least one cisplatin-containing chemotherapy regimen or contraindication to cytotoxic drugs, Eastern Cooperative Oncology Group performance status < or =2, and adequate hematological, renal and hepatic parameters. All patients provided signed informed consent. Patient re-evaluation was performed every 4-6 weeks. RESULTS: Seventy-three consecutive patients were enrolled. Response rate, including complete and partial response, was 9.6%; an additional 43.8% of patients achieved stable disease, for an overall disease control of 53.4%. EGFR1 status was evaluated by immunocytochemistry in 25 patients. According to EGFR1 immunoreactivity all responses were observed with medium/strong imunoreactivity while three out of four responses were observed in high expressive patients. Median survival for all patients was 4 months while it reached 6 months for patients with disease control. The 1-year survival rate was 13.1% for the entire series and 23.2% for patients with disease control. Non-hematological toxicity was generally mild. CONCLUSION: Gefitinib has promising activity with a good toxicity profile in patients with progressive NSCLC who have received one or two prior chemotherapy regimens. A possible relationship within response and EGFR1 expression is suggested.     

Epidermal growth factor receptor mutations detected by denaturing high‐performance liquid chromatography in nonsmall cell lung cancer

BACKGROUND:

Somatic mutations in the epidermal growth factor receptor (EGFR) kinase domain are associated with sensitivity to EGFR‐tyrosine kinase inhibitors (EGFR‐TKI) in patients with nonsmall cell lung cancer (NSCLC).

METHODS:

The authors tested the possibility that nucleotide sequencing may be poorly suited for detection of mutations in tumor samples and found that denaturing high‐performance liquid chromatography (dHPLC) was an efficient and more sensitive method for screening.

RESULTS:

These results suggested that some reports based on standard DNA sequencing techniques may have underestimated mutation rates. In the present report, the authors examined the relationship between the presence and type of EGFR mutations detected by dHPLC and various clinicopathologic features of NSCLC, including response to therapy with EGFR‐TKI. Among 251 patients with advanced disease, 100 individuals received EGFR‐TKI. Those whose tumors harbored a detectable EGFR kinase mutation were much more likely to have a partial response (PR) or stable disease (SD) with EGFR‐TKI therapy than patients whose tumor contained no mutation (80% vs 35%; P = .001). Among the individual genotype subgroups, the frequency of a PR or SD was significantly different between patients with an exon 19 deletion compared with those with no detectable mutation (86% vs 35%; P < .001). Furthermore, patients whose tumors expressed an exon 19 mutant EGFR isoform exhibited a trend toward better EGFR‐TKI response (86% vs 67%; P = .171) and improved survival compared with patients whose tumors expressed an exon 21 mutation.

CONCLUSIONS:

Our findings warrant confirmation in large prospective trials and exploration of the biological mechanisms of the differences between mutation types. Cancer 2010. © 2010 American Cancer Society.     

Preanalytic parameters in epidermal growth factor receptor mutation testing for non–small cell lung carcinoma: A review of cytologic series

The results from molecular assays can be affected significantly by the preanalytic condition of cytologic samples. The authors review current knowledge on the use of cytologic samples for epidermal growth factor receptor (EGFR) mutation testing in non–small cell lung cancer with a focus on preanalytic parameters. A systematic electronic search of the MEDLINE database was performed to identify original articles that reported the use of cytologic samples for EGFR molecular analysis and included a minimum of 100 samples. The information collected included author(s), journal, and year of publication; number of patients and samples; sampling method; type of preparation; type of fixative; staining techniques; mutation analysis techniques; tumor cellularity; the percentage of tumor cells; data on DNA quantity, quality, and concentration; failed assays; and the mutation rate. EGFR mutation analysis was conducted on 4999 cytologic samples from 22 studies that fulfilled the inclusion criteria. Fine‐needle aspirates and pleural effusions were the most common types of specimens used. DNA was mainly extracted from cell blocks and smears, and the most commonly reported fixatives included formalin, ethanol, and CytoLyt. Cellularity assessments and DNA yields were available from 5 studies each. The average success rate for the assays that used cytologic specimens was 95.87% (range, 85.2%‐100%). The mutation rate ranged from 6% to 50.46%, and a higher mutation detection rate and lower numbers of insufficient cases were reported for pleural effusions and lymph node samples from endobronchial ultrasound‐guided transbronchial needle aspiration compared with histologic specimens. Low cellularity and a low percentage of tumor cells were associated with higher test failure rates. Future guidelines should consider the current data for specific recommendations regarding cytologic samples. Cancer (Cancer Cytopathol) 2015;123:633–643 . © 2015 American Cancer Society.     

免疫检查点抑制剂治疗EGFR-TKI耐药晚期非小细胞肺癌的疗效及不良反应

目的:探讨免疫检查点抑制剂(immune checkpoint inhibitor,ICI)治疗表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitor,EGFR-TKI)耐药晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的疗效及不良反应。方法:收集2015年1月至2019年3月在解放军总医院接受ICI治疗的EGFR-TKI耐药晚期NSCLC患者临床资料,采用统计学方法分析EGFR-TKI耐药晚期NSCLC患者免疫治疗疗效及不良反应,阐明临床特征与免疫治疗疗效和患者预后的关系。结果:联合治疗较单药治疗者肿瘤客观缓解率(objective response rate,ORR)显著提高(28.6%vs.7.1%,P<0.01)。肿瘤分化差、联合治疗及年龄>60岁者分别较肿瘤分化好(5.1个月vs.2.8个月,P=0.030)、单药治疗(6.8个月vs.2.3个月,P<0.001)及年龄≤60岁者(7.1个月vs.4.7个月,P=0.020)无进展生存期(progression free survival,PFS)延长。联合治疗、肿瘤治疗缓解者分别较单药治疗(26.9个月vs.7.1个月)、肿瘤稳定者和进展者(30.8个月vs.18.7个月vs.12.8个月)总生存期(overall survival,OS)延长(P<0.001)。多因素分析显示年龄>60岁和联合治疗是PFS独立保护性因素(P<0.001)。联合治疗组的总体不良反应发生率较单药治疗组升高,但≥3级不良反应发生率两组间无显著性差异(P=0.28)。结论:ICI单药治疗EGFR-TKI耐药晚期NSCLC患者的疗效较差,而联合治疗能显著提高疗效,改善患者的预后。尽管联合治疗的总体不良反应发生率较高,但大体上不良反应可控。