表皮生长因子受体阳性非小细胞肺癌脑转移患者靶向联合治疗研究进展

doi:10.12114/j.issn.1007-9572.2024.0101

摘要/Abstract

摘要： 脑转移是非小细胞肺癌（NSCLC）患者预后不良的主要因素，其在表皮生长因子受体（EGFR）突变的NSCLC患者中发生率更高。针对EGFR靶点的酪氨酸激酶抑制剂（EGFR-TKI）因其优异的疗效及安全性，已成为EGFR阳性NSCLC稳定脑转移患者的一线治疗用药，尤其是第三代EGFR-TKI。本文针对EGFR突变NSCLC脑转移患者单药EGFR-TKI及联合治疗的疗效、安全性以及未来挑战做出综述，得出EGFR-TKI联合化疗可能是EGFR阳性NSCLC脑转移患者的潜在替代治疗方案，尤其是对于亚洲患者；而对于EGFR-TKI联合抗血管生成或放疗，联合治疗的额外获益并不明显，后续可根据EGFR突变类型、合并突变、临床病理特征等分层因素开展大型前瞻性研究进一步验证并寻找个体化的治疗方案；EGFR-TKI联合免疫治疗的安全性仍需要进一步探索。

关键词: 非小细胞肺癌, 表皮生长因子受体, 脑转移, 酪氨酸激酶抑制剂, 联合治疗

Abstract:

Brain metastases are a major factor in the poor prognosis of patients with non-small cell lung cancer. The incidence of brain metastases is higher in patients with EGFR-mutated non-small cell lung cancer, and tyrosine kinase inhibitors targeting it have become the first-line treatment for patients with stable brain metastases from EGFR-mutated NSCLC due to their excellent efficacy and safety, especially third-generation EGFR-TKIs. This article provided a review of the efficacy, safety, and future challenges of single-agent EGFR-TKIs and combination therapy in patients with brain metastases from EGFR-mutant non-small cell lung cancer. This article suggested that EGFR-TKI in combination with chemotherapy might be a potential alternative treatment option for patients with EGFR-mutated NSCLC brain metastases, especially for Asian patients, whereas for EGFR-TKI in combination with antiangiogenic or radiotherapy, the frontal benefit of the combination therapy was not obvious, and large prospective studies could be conducted to further validate and find individualized treatment options based on stratification factors such as EGFR mutation type, comorbid mutations, and clinicopathological features. As for EGFR-TKI combined with immunotherapy, the safety of the combined treatment still needed to be further explored.

Key words: Non-small cell lung cancer, Epidermal growth factor receptor, Brain metastases, Tyrosine kinase inhibitors, Combination therapy

中图分类号:

R 730.26

王亚静,段晓阳,侯冉,等. 表皮生长因子受体阳性非小细胞肺癌脑转移患者靶向联合治疗研究进展[J]. 中国全科医学, 2025, 28(26): 3328-3337. DOI: 10.12114/j.issn.1007-9572.2024.0101.
WANG Yajing,DUAN Xiaoyang,HOU Ran, et al. Advances in Targeted Combination Therapy for Patients with Brain Metastases from EGFR-mutated Non-small Cell Lung Cancer[J]. Chinese General Practice, 2025, 28(26): 3328-3337. DOI: 10.12114/j.issn.1007-9572.2024.0101.

图/表 1

参考文献 80

[1]	SIEGEL R L，MILLER K D，FUCHS H E，et al. Cancer statistics，2022[J]. CA Cancer J Clin，2022，72（1）：7-33. DOI：10.3322/caac.21708.
[2]	SPERDUTO P W，De B，LI J，et al. Graded prognostic assessment（GPA）for patients with lung cancer and brain metastases：initial report of the small cell lung cancer GPA and update of the non-small cell lung cancer GPA including the effect of programmed death ligand 1 and other prognostic factors[J]. Int J Radiat Oncol Biol Phys，2022，114（1）：60-74. DOI：10.1016/j.ijrobp.2022.03.020.
[3]	PAN K，CONCANNON K，LI J，et al. Emerging therapeutics and evolving assessment criteria for intracranial metastases in patients with oncogene-driven non-small-cell lung cancer[J]. Nat Rev Clin Oncol，2023，20（10）：716-732. DOI：10.1038/s41571-023-00808-4.
[4]	MA Y，CHEN K，YANG Z，et al. Targeted sequencing reveals distinct pathogenic variants in chinese patients with lung adenocarcinoma brain metastases[J]. Oncol Lett，2018，15（4）：4503-4510. DOI：10.3892/ol.2018.7859.
[5]	GEISSLER M，JIA W，KIRAZ E N，et al. The brain pre-metastatic niche：biological and technical advancements[J]. Int J Mol Sci，2023，24（12）. DOI：10.3390/ijms241210055.
[6]	SINGH M，GARG N，VENUGOPAL C，et al. STAT3 pathway regulates lung-derived brain metastasis initiating cell capacity through mir-21 activation[J]. Oncotarget，2015，6（29）：27461-27477. DOI：10.18632/oncotarget.4742.
[7]	LI H，TONG F，MENG R，et al. E2F1-mediated repression of WNT5a expression promotes brain metastasis dependent on the ERK1/2 pathway in EGFR-mutant non-small cell lung cancer[J]. Cell Mol Life Sci，2021，78（6）：2877-2891. DOI：10.1007/s00018-020-03678-6.
[8]	BURNS T F，DACIC S，VELEZ M A，et al. Abstract 2218：MET alterations are enriched in lung adenocarcinoma brain metastases and define a distinct molecular and transcriptomic subtype[Z]. 2021.
[9]	ZHOU Y，WANG B，QU J，et al. Survival outcomes and symptomatic central nervous system（cns）metastasis in EGFR-mutant advanced non-small cell lung cancer without baseline CNS metastasis：osimertinib vs. First-generation EGFR tyrosine kinase inhibitors[J]. Lung Cancer，2020，150：178-185. DOI：10.1016/j.lungcan.2020.10.018.
[10]	WANG H，WANG Z，ZHANG G，et al. Driver genes as predictive indicators of brain metastasis in patients with advanced NSCLC：EGFR，ALK，and RET gene mutations[J]. Cancer Med，2020，9（2）：487-495. DOI：10.1002/cam4.2706.
[11]	CHEN B T，JIN T，YE N，et al. Differential distribution of brain metastases from non-small cell lung cancer based on mutation status[J]. Brain Sci，2023，13（7）. DOI：10.3390/brainsci13071057.
[12]	YANG J J，ZHOU C，HUANG Y，et al. Icotinib versus whole-brain irradiation in patients with EGFR-mutant non-small-cell lung cancer and multiple brain metastases（brain）：a multicentre，phase 3，open-label，parallel，randomised controlled trial[J]. Lancet Respir Med，2017，5（9）：707-716. DOI：10.1016/S2213-2600(17)30262-X.
[13]	ZHANG J，YU J，SUN X，et al. Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of central nerve system metastases from non-small cell lung cancer[J]. Cancer Lett，2014，351（1）：6-12. DOI：10.1016/j.canlet.2014.04.019.
[14]	AIKO N，SHIMOKAWA T，MIYAZAKI K，et al. Comparison of the efficacies of first-generation epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in patients with advanced non-small-cell lung cancer harboring EGFR mutations[J]. BMC Cancer，2018，18（1）：1012. DOI：10.1186/s12885-018-4911-7.
[15]	BALLARD P，YATES J W，YANG Z，et al. Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models，and early evidence of clinical brain metastases activity[J]. Clin Cancer Res，2016，22（20）：5130-5140. DOI：10.1158/1078-0432.CCR-16-0399.
[16]	HU X，ZHANG S，MA Z，et al. Central nervous system efficacy of furmonertinib（ast2818）in patients with EGFR t790m mutated non-small cell lung cancer：a pooled analysis from two phase 2 studies[J]. BMC Med，2023，21（1）：164. DOI：10.1186/s12916-023-02865-z.
[17]	SHI Y，CHEN G，WANG X，et al. Central nervous system efficacy of furmonertinib（ast2818）versus gefitinib as first-line treatment for EGFR-mutated NSCLC：results from the furlong study[J]. J Thorac Oncol，2022，17（11）：1297-1305. DOI：10.1016/j.jtho.2022.07.1143.
[18]	LU S，WANG Q，ZHANG G，et al. Efficacy of aumolertinib（hs-10296）in patients with advanced EGFR t790m+ NSCLC：updated post-national medical products administration approval results from the apollo registrational trial[J]. J Thorac Oncol，2022，17（3）：411-422. DOI：10.1016/j.jtho.2021.10.024.
[19]	LU S，DONG X，JIAN H，et al. Aumolertinib activity in patients with CNS metastases and EGFR-mutated NSCLC treated in the randomized double-blind phase iii trial（aeneas）[Z]. 2022.
[20]	ERICKSON A W，BRASTIANOS P K，DAS S. Assessment of effectiveness and safety of osimertinib for patients with intracranial metastatic disease：a systematic review and meta-analysis[J]. JAMA Netw Open，2020，3（3）：e201617. DOI：10.1001/jamanetworkopen.2020.1617.
[21]	REUNGWETWATTANA T，NAKAGAWA K，CHO B C，et al. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer[J]. J Clin Oncol，2018：JCO2018783118. DOI：10.1200/JCO.2018.78.3118.
[22]	YANG Z，GUO Q，WANG Y，et al. Azd3759，a BBB-penetrating EGFR inhibitor for the treatment of EGFR mutant NSCLC with CNS metastases[J]. Sci Transl Med，2016，8（368）：368ra172. DOI：10.1126/scitranslmed.aag0976.
[23]	WU Y，ZHOU Q，WANG J，et al. Randomized phase 3 study of first-line AZD3759（zorifertinib）versus gefitinib or erlotinib in EGFR-mutant（EGFRm+）non-small-cell lung cancer（NSCLC）with central nervous system（CNS）metastasis[J]. Journal of Clinical Oncology，2023，41（16_suppl）：9001. DOI：10.1200/JCO.2023.41.16_suppl.9001.
[24]	MAGGIE L S，DONG X R，WANG Z，et al. Efficacy，safety and dose selection of AZD3759 in patients with untreated EGFR-mutated non-small-cell lung cancer and central nervous system metastases in China（CTONG1702-Arm 8）：a multi-center，single-arm，phase 2 trial[J]. EClinicalMedicine，2023，64：102238. DOI：10.1016/j.eclinm.2023.102238.
[25]	CONTI C，CAMPBELL J，WOESSNER R，et al. Abstract 1262：BLU-701 is a highly potent，brain-penetrant and WT-sparing next-generation EGFR TKI for the treatment of sensitizing（ex19del，l858r）and c797s resistance mutations in metastatic NSCLC[Z]. 2021.
[26]	LUCAS M，MERCHANT M，O'CONNOR M，et al. 27mo BDTX-1535，a CNS penetrant，irreversible inhibitor of intrinsic and acquired resistance egfr mutations，demonstrates preclinical efficacy in NSCLC and GBM PDX models[J]. Ann Oncol，2022，33（S1）：S14.
[27]	YU X，FAN Y. Effect of pemetrexed on brain metastases from nonsmall cell lung cancer with wild-type and unknown EGFR status[J]. Medicine（Baltimore），2019，98（3）：e14110. DOI：10.1097/MD.0000000000014110.
[28]	AO L，FANG S，ZHANG K，et al. Sequence-dependent synergistic effect of aumolertinib-pemetrexed combined therapy on EGFR-mutant non-small-cell lung carcinoma with pre-clinical and clinical evidence[J]. J Exp Clin Cancer Res，2022，41（1）：163. DOI：10.1186/s13046-022-02369-3.
[29]	HOU X，LI M，WU G，et al. Gefitinib plus chemotherapy vs gefitinib alone in untreated EGFR-mutant non-small cell lung cancer in patients with brain metastases：the gap brain open-label，randomized，multicenter，phase 3 study[J]. JAMA Netw Open，2023，6（2）：e2255050. DOI：10.1001/jamanetworkopen.2022.55050.
[30]	DAI L，LUO C Y，HU G X，et al. Comparative analysis of first-line treatment regimens for advanced EGFR-mutant non-small cell lung cancer patients with stable brain metastases[J]. Ann Palliat Med，2020，9（4）：2062-2071. DOI：10.21037/apm-20-1136.
[31]	JÄNNE P A，PLANCHARD D，KOBAYASHI K，et al. CNS efficacy of osimertinib with or without chemotherapy in epidermal growth factor receptor-mutated advanced non-small-cell lung cancer[J]. J Clin Oncol，2023：JCO2302219. DOI：10.1200/JCO.23.02219.
[32]	OIZUMI S，SUGAWARA S，MINATO K，et al. Updated survival outcomes of NEJ005/TCOG0902：a randomised phaseⅡ study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations[J]. ESMO Open，2018，3（2）：e313. DOI：10.1136/esmoopen-2017-000313.
[33]	LARSEN A K，OUARET D，EL O K，et al. Targeting EGFR and VEGF（R） pathway cross-talk in tumor survival and angiogenesis[J]. Pharmacol Ther，2011，131（1）：80-90. DOI：10.1016/j.pharmthera.2011.03.012.
[34]	FENG P H，CHEN K Y，HUANG Y C，et al. Bevacizumab reduces s100a9-positive MDSCs linked to intracranial control in patients with EGFR-mutant lung adenocarcinoma[J]. J Thorac Oncol，2018，13（7）：958-967. DOI：10.1016/j.jtho.2018.03.032.
[35]	ZHOU Q，XU C R，CHENG Y，et al. Bevacizumab plus erlotinib in chinese patients with untreated，EGFR-mutated，advanced NSCLC（artemis-ctong1509）：a multicenter phase 3 study[J]. Cancer Cell，2021，39（9）：1279-1291. DOI：10.1016/j.ccell.2021.07.005.
[36]	HU D，ZHOU Y Y，MA H B，et al. Efficacy and safety of EGFR-TKIs in combination with angiogenesis inhibitors as first-line therapy for advanced EGFR-mutant non-small-cell lung cancer：a systematic review and meta-analysis[J]. BMC Pulm Med，2023，23（1）：207. DOI：10.1186/s12890-023-02472-x.
[37]	JIANG T，ZHANG Y，LI X，et al. EGFR-TKIs plus bevacizumab demonstrated survival benefit than EGFR-TKIs alone in patients with EGFR-mutant nsclc and multiple brain metastases[J]. Eur J Cancer，2019，121：98-108. DOI：10.1016/j.ejca.2019.08.021.
[38]	CHIKAISHI Y，KANAYAMA M，TAIRA A，et al. Effect of erlotinib plus bevacizumab on brain metastases in patients with non-small cell lung cancer[J]. Ann Transl Med，2018，6（20）：401. DOI：10.21037/atm.2018.09.33.
[39]	ZHAO H，YAO W，MIN X，et al. Apatinib plus gefitinib as first-line treatment in advanced EGFR-mutant nsclc：the phase Ⅲactive study（CTONG1706）[J]. J Thorac Oncol，2021，16（9）：1533-1546. DOI：10.1016/j.jtho.2021.05.006.
[40]	KENMOTSU H，WAKUDA K，MORI K，et al. Randomized phase 2 study of osimertinib plus bevacizumab versus osimertinib for untreated patients with nonsquamous NSCLC harboring EGFR mutations：WJOG9717L study[J]. J Thorac Oncol，2022，17（9）：1098-1108. DOI：10.1016/j.jtho.2022.05.006.
[41]	KAWASHIMA Y，FUKUHARA T，SAITO H，et al. Bevacizumab plus erlotinib versus erlotinib alone in japanese patients with advanced，metastatic，EGFR-mutant non-small-cell lung cancer（NEJ026）：overall survival analysis of an open-label，randomised，multicentre，phase 3 trial[J]. Lancet Respir Med，2022，10（1）：72-82. DOI：10.1016/S2213-2600(21)00166-1.
[42]	CHIU T H，TUNG P H，HUANG C H，et al. The different overall survival between single-agent EGFR-TKI treatment and with bevacizumab in non-small cell lung cancer patients with brain metastasis[J]. Sci Rep，2022，12（1）：4398. DOI：10.1038/s41598-022-08449-w.
[43]	GRIDELLI C，de CASTRO C J，DINGEMANS A C，et al. Safety and efficacy of bevacizumab plus standard-of-care treatment beyond disease progression in patients with advanced non-small cell lung cancer：the avaall randomized clinical trial[J]. JAMA Oncol，2018，4（12）：e183486. DOI：10.1001/jamaoncol.2018.3486.
[44]	ZHANG Y，LI Y，HAN Y，et al. Experimental study of EGFR-TKI aumolertinib combined with ionizing radiation in EGFR mutated NSCLC brain metastases tumor[J]. Eur J Pharmacol，2023，945：175571. DOI：10.1016/j.ejphar.2023.175571.
[45]	LIU B，LIU H，MA Y，et al. EGFR-mutated stage Ⅳ non-small cell lung cancer：what is the role of radiotherapy combined with TKI？[J]. Cancer Med，2021，10（18）：6167-6188. DOI：10.1002/cam4.4192.
[46]	SONG Y，LIN S，CHEN J，et al. First-line treatment with TKI plus brain radiotherapy versus TKI alone in EGFR-mutated non-small cell lung cancer with brain metastases：a systematic review and meta-analysis[J]. BMC Cancer，2023，23（1）：1043. DOI：10.1186/s12885-023-11548-0.
[47]	HE Z Y，LI M F，LIN J H，et al. Comparing the efficacy of concurrent EGFR-TKI and whole-brain radiotherapy vs EGFR-TKI alone as a first-line therapy for advanced egfr-mutated non-small-cell lung cancer with brain metastases：a retrospective cohort study[J]. Cancer Manag Res，2019，11：2129-2138. DOI：10.2147/CMAR.S184922.
[48]	YU F，NI J，ZENG W，et al. Clinical value of upfront cranial radiation therapy in osimertinib-treated epidermal growth factor receptor-mutant non-small cell lung cancer with brain metastases[J]. Int J Radiat Oncol Biol Phys，2021，111（3）：804-815. DOI：10.1016/j.ijrobp.2021.05.125.
[49]	THOMAS N J，MYALL N J，SUN F，et al. Brain metastases in EGFR-and ALK-positive NSCLC：outcomes of central nervous system-penetrant tyrosine kinase inhibitors alone versus in combination with radiation[J]. J Thorac Oncol，2022，17（1）：116-129. DOI：10.1016/j.jtho.2021.08.009.
[50]	ZHAI X，LI W，LI J，et al. Therapeutic effect of osimertinib plus cranial radiotherapy compared to osimertinib alone in NSCLC patients with EGFR-activating mutations and brain metastases：a retrospective study[J]. Radiat Oncol，2021，16（1）：233. DOI：10.1186/s13014-021-01955-7.
[51]	HUI C，POLLOM E L，LI G，et al. Advancements without consensus：differing practice patterns highlight unanswered questions in the management of brain metastases from EGFR-and ALK-positive non-small cell lung cancer[J]. J Thorac Dis，2023，15（11）：5877-5884. DOI：10.21037/jtd-23-1483.
[52]	YAMAMOTO M，SERIZAWA T，HIGUCHI Y，et al. A multi-institutional prospective observational study of stereotactic radiosurgery for patients with multiple brain metastases（JLGK0901 study update）：irradiation-related complications and long-term maintenance of mini-mental state examination scores[J]. Int J Radiat Oncol Biol Phys，2017，99（1）：31-40. DOI：10.1016/j.ijrobp.2017.04.037.
[53]	MAGNUSON W J，LESTER-COLL N H，WU A J，et al. Management of brain metastases in tyrosine kinase inhibitor-naïve epidermal growth factor receptor-mutant non-small-cell lung cancer：a retrospective multi-institutional analysis[J]. J Clin Oncol，2017，35（10）：1070-1077. DOI：10.1200/JCO.2016.69.7144.
[54]	LIU S，QIU B，CHEN L，et al. Radiotherapy for asymptomatic brain metastasis in epidermal growth factor receptor mutant non-small cell lung cancer without prior tyrosine kinase inhibitors treatment：a retrospective clinical study[J]. Radiat Oncol，2015，10：118. DOI：10.1186/s13014-015-0421-9.
[55]	LIANG S，LIU X，LIU J，et al. Optimal timing of hypofractionated stereotactic radiotherapy for epidermal growth factor receptor-mutated non-small-cell lung cancer patients with brain metastases[J]. Asia Pac J Clin Oncol，2023，19（6）：731-738. DOI：10.1111/ajco.13957.
[56]	NORONHA V，PATIL V M，JOSHI A，et al. Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer[J]. J Clin Oncol，2020，38（2）：124-136. DOI：10.1200/JCO.19.01154.
[57]	MIYAUCHI E，MORITA S，NAKAMURA A，et al. Updated analysis of NEJ009：gefitinib-alone versus gefitinib plus chemotherapy for non-small-cell lung cancer with mutated EGFR[J]. J Clin Oncol，2022，40（31）：3587-3592. DOI：10.1200/JCO.21.02911.
[58]	LEE Y，KIM H R，HONG M H，et al. A randomized phase 2 study to compare erlotinib with or without bevacizumab in previously untreated patients with advanced non-small cell lung cancer with EGFR mutation[J]. Cancer，2023，129（3）：405-414. DOI：10.1002/cncr.34553.
[59]	NINOMIYA T，ISHIKAWA N，KOZUKI T，et al. A randomized phaseⅡ study of afatinib alone or combined with bevacizumab for treating chemo-naïve patients with non-small cell lung cancer harboring EGFR mutations[J]. Lung Cancer，2023，184：107349. DOI：10.1016/j.lungcan.2023.107349.
[60]	PENG P，GONG J，ZHANG Y，et al. EGFR-TKIs plus stereotactic body radiation therapy（SBRT）for stage iv non-small cell lung cancer（NSCLC）：a prospective，multicenter，randomized，controlled phaseⅡ study[J]. Radiother Oncol，2023，184：109681. DOI：10.1016/j.radonc.2023.109681.
[61]	LIZOTTE P H，HONG R L，LUSTER T A，et al. A high-throughput immune-oncology screen identifies egfr inhibitors as potent enhancers of antigen-specific cytotoxic T-lymphocyte tumor cell killing[J]. Cancer Immunol Res，2018，6（12）：1511-1523. DOI：10.1158/2326-6066.CIR-18-0193.
[62]	WIEST N，MAJEED U，SEEGOBIN K，et al. Role of immune checkpoint inhibitor therapy in advanced EGFR-mutant non-small cell lung cancer[J]. Front Oncol，2021，11：751209. DOI：10.3389/fonc.2021.751209.
[63]	OKADA N，HAMANO H，YAGI K，et al. Effect of pre-treatment with EGFR-TKIs on immune checkpoint inhibitor-associated interstitial lung disease in lung cancer patients：analysis using a japanese claims database[J]. Int J Clin Pharmacol Ther，2024，62（2）：69-76. DOI：10.5414/CP204491.
[64]	LE X，NEGRAO M V，REUBEN A，et al. Characterization of the immune landscape of EGFR-mutant NSCLC identifies cd73/adenosine pathway as a potential therapeutic target[J]. J Thorac Oncol，2021，16（4）：583-600. DOI：10.1016/j.jtho.2020.12.010.
[65]	JIA Y，LI X，JIANG T，et al. Egfr-targeted therapy alters the tumor microenvironment in EGFR-driven lung tumors：implications for combination therapies[J]. Int J Cancer，2019，145（5）：1432-1444. DOI：10.1002/ijc.32191.
[66]	DOMINGUEZ C，TSANG K Y，PALENA C. Short-term EGFR blockade enhances immune-mediated cytotoxicity of egfr mutant lung cancer cells：rationale for combination therapies[J]. Cell Death Dis，2016，7（9）：e2380. DOI：10.1038/cddis.2016.297.
[67]	QIAO M，JIANG T，LIU X，et al. Immune checkpoint inhibitors in EGFR-mutated nsclc：dusk or dawn?[J]. J Thorac Oncol，2021，16（8）：1267-1288. DOI：10.1016/j.jtho.2021.04.003.
[68]	DONG Z Y，ZHANG J T，LIU S Y，et al. EGFR mutation correlates with uninflamed phenotype and weak immunogenicity，causing impaired response to PD-1 blockade in non-small cell lung cancer[J]. Oncoimmunology，2017，6（11）：e1356145. DOI：10.1080/2162402X.2017.1356145.
[69]	CREELAN B C，YEH T，KIM S W，et al. Phase i study of gefitinib（G）+ durvalumab（D）for locally advanced/metastatic non-small cell lung cancer（NSCLC）harbouring epidermal growth factor receptor（EGFR）sensitising mutations[J]. Annals of Oncology，2019，30：ii31-ii32. DOI：10.1093/annonc/mdz067.001.
[70]	MAZIERES J，DRILON A，LUSQUE A，et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations：results from the immunotarget registry[J]. Ann Oncol，2019，30（8）：1321-1328. DOI：10.1093/annonc/mdz167.
[71]	LIU S，WU F，LI X，et al. Patients with short PFS to EGFR-TKIs predicted better response to subsequent anti-PD-1/PD-L1 based immunotherapy in EGFR common mutation nsclc[J]. Front Oncol，2021，11：639947. DOI：10.3389/fonc.2021.639947.
[72]	ZHOU J，YU X，HOU L，et al. Epidermal growth factor receptor tyrosine kinase inhibitor remodels tumor microenvironment by upregulating LAG-3 in advanced non-small-cell lung cancer[J]. Lung Cancer，2021，153：143-149. DOI：10.1016/j.lungcan.2021.01.010.
[73]	CHEN K，CHENG G，ZHANG F，et al. PD-L1 expression and t cells infiltration in patients with uncommon EGFR-mutant non-small cell lung cancer and the response to immunotherapy[J]. Lung Cancer，2020，142：98-105. DOI：10.1016/j.lungcan.2020.02.010.
[74]	YAMADA T，HIRAI S，KATAYAMA Y，et al. Retrospective efficacy analysis of immune checkpoint inhibitors in patients with EGFR-mutated non-small cell lung cancer[J]. Cancer Med，2019，8（4）：1521-1529. DOI：10.1002/cam4.2037.
[75]	SI J，HAO Y，WEI J，et al. Clinical outcomes of immune checkpoint inhibitors to treat non-small cell lung cancer patients harboring epidermal growth factor receptor mutations[J]. BMC Pulm Med，2023，23（1）：158. DOI：10.1186/s12890-023-02466-9.
[76]	CAI R，LIU Y，YU M，et al. A retrospective real-world study：the efficacy of immune-related combination therapies in advanced non-small cell lung cancer after resistance to EGFR-TKIs[J]. Cancer Immunol Immunother，2023，72（12）：4355-4365. DOI：10.1007/s00262-023-03570-9.
[77]	WANG Z，ZHOU F，XU S，et al. The efficacy and safety of immune checkpoint inhibitors for patients with EGFR-mutated non-small cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor therapy：a systematic review and network meta-analysis[J]. Cancer Med，2023，12（18）：18516-18530. DOI：10.1002/cam4.6453.
[78]	YANG H，WEN L，ZHAO C，et al. Cerebrospinal fluid-derived circulating tumor dna is more comprehensive than plasma in NSCLC patients with leptomeningeal metastases regardless of extracranial evolution[J]. Heliyon，2022，8（12）：e12374. DOI：10.1016/j.heliyon.2022.e12374.
[79]	FAN Y，ZHU X，XU Y，et al. Cell-cycle and DNA-damage response pathway is involved in leptomeningeal metastasis of non-small cell lung cancer[J]. Clin Cancer Res，2018，24（1）：209-216. DOI：10.1158/1078-0432.CCR-17-1582.
[80]	LI M，CHEN J，ZHANG B，et al. Dynamic monitoring of cerebrospinal fluid circulating tumor dna to identify unique genetic profiles of brain metastatic tumors and better predict intracranial tumor responses in non-small cell lung cancer patients with brain metastases：a prospective cohort study（GASTO 1028）[J]. BMC Med，2022，20（1）：398. DOI：10.1186/s12916-022-02595-8.

试验	发表时间（年）	设计	干预措施	PFS[HR（95%CI）]	OS[HR（95%CI）]
EGFR-TKI联合化疗
NORONHA^[56]	2019	Ⅲ期RCT	G+培美曲塞和卡铂（30） G（34）	0.53（0.29~0.98）
MIYAUCHI^[57]	2022	Ⅲ期RCT	G+培美曲塞和卡铂（50） G（38）	0.32（0.19~0.53）	0.73（0.47~1.16）
HOU^[29]	2023	Ⅲ期RCT	G+培美曲塞和顺铂/奈达铂（81） G（80）	0.39（0.27~0.58）	0.65（0.43~0.99）
JÄNNE^[31]	2023	Ⅲ期RCT	O+培美曲塞和顺铂/卡铂（116） O（110）	0.47（0.33~0.66）
EGFR-TKI联合抗血管
ZHAO^[39]	2021	Ⅲ期RCT	G+阿帕替尼（51） G（41）	0.91（0.50~1.64）
KENMOTSU^[40]	2022	Ⅱ期RCT	O+贝伐珠单抗（18） O（23）	0.833（0.359~1.935）
KAWASHIMA^[41]	2021	Ⅲ期RCT	E+贝伐珠单抗（36） E（36）	0.78（0.42~1.43）	0.839（0.432~1.629）
ZHOU^[35]	2021	Ⅲ期RCT	E+贝伐珠单抗（44） E（47）	0.48（0.27~0.84）	0.62（0.38~1.01）
LEE^[58]	2022	Ⅱ期RCT	E+贝伐珠单抗（29） E（30）	0.54（0.31~0.95）	1.27（0.58~2.79）
NINOMIYA^[59]	2023	Ⅱ期RCT	Afa+贝伐珠单抗（13） Afa（19）	0.52（0.204~1.328）
EGFR-TKI联合放疗
PENG^[60]	2023	Ⅱ期RCT	一代EGFR-TKI+SBRT（31）一代EGFR-TKI（31）	0.52（0.31~0.89）	0.53（0.30~0.95）

试验	发表时间（年）	设计	干预措施	PFS[HR（95%CI）]	OS[HR（95%CI）]
EGFR-TKI联合化疗
NORONHA^[56]	2019	Ⅲ期RCT	G+培美曲塞和卡铂（30） G（34）	0.53（0.29~0.98）
MIYAUCHI^[57]	2022	Ⅲ期RCT	G+培美曲塞和卡铂（50） G（38）	0.32（0.19~0.53）	0.73（0.47~1.16）
HOU^[29]	2023	Ⅲ期RCT	G+培美曲塞和顺铂/奈达铂（81） G（80）	0.39（0.27~0.58）	0.65（0.43~0.99）
JÄNNE^[31]	2023	Ⅲ期RCT	O+培美曲塞和顺铂/卡铂（116） O（110）	0.47（0.33~0.66）
EGFR-TKI联合抗血管
ZHAO^[39]	2021	Ⅲ期RCT	G+阿帕替尼（51） G（41）	0.91（0.50~1.64）
KENMOTSU^[40]	2022	Ⅱ期RCT	O+贝伐珠单抗（18） O（23）	0.833（0.359~1.935）
KAWASHIMA^[41]	2021	Ⅲ期RCT	E+贝伐珠单抗（36） E（36）	0.78（0.42~1.43）	0.839（0.432~1.629）
ZHOU^[35]	2021	Ⅲ期RCT	E+贝伐珠单抗（44） E（47）	0.48（0.27~0.84）	0.62（0.38~1.01）
LEE^[58]	2022	Ⅱ期RCT	E+贝伐珠单抗（29） E（30）	0.54（0.31~0.95）	1.27（0.58~2.79）
NINOMIYA^[59]	2023	Ⅱ期RCT	Afa+贝伐珠单抗（13） Afa（19）	0.52（0.204~1.328）
EGFR-TKI联合放疗
PENG^[60]	2023	Ⅱ期RCT	一代EGFR-TKI+SBRT（31）一代EGFR-TKI（31）	0.52（0.31~0.89）	0.53（0.30~0.95）