收稿日期: 2022-09-30
录用日期: 2023-03-14
网络出版日期: 2023-07-11
基金资助
国家自然科学基金(82030045);北京市希思科临床肿瘤学研究基金会(Y-HR2020MS-0982)
Advances in immunotherapy of advanced non-small cell lung cancer with EGFR mutation
Received date: 2022-09-30
Accepted date: 2023-03-14
Online published: 2023-07-11
Supported by
National Natural Science Foundation of China(82030045);Beijing Xisike Clinical Oncology Research Foundation(Y-HR2020MS-0982)
亚洲人群非小细胞肺癌（non-small cell lung cancer，NSCLC）表皮生长因子受体（epidermal growth factor receptor，EGFR）突变发生率显著高于西方人群。近年来，以针对程序性死亡因子1（programmed cell death 1，PD-1）及程序性死亡因子配体1（programmed cell death ligand 1，PD-L1）抗体药物为代表的免疫治疗已成为晚期NSCLC临床治疗方案之一，开启肺癌免疫治疗新时代；然而既往研究报道EGFR突变型晚期NSCLC患者未能从免疫治疗单药中获益，不同EGFR突变型的患者对免疫治疗的响应也存在差异。最新临床研究ORIENT-31中期分析结果显示，免疫治疗联合化疗和抗血管生成药物显著改善了EGFR酪氨酸激酶抑制剂耐药的晚期NSCLC患者的无进展生存期，为此类EGFR突变型患者提供了新的临床治疗策略。EGFR突变型肿瘤组织微环境呈免疫抑制的状态，通过靶向肿瘤免疫抑制中发挥重要作用的靶点，促进EGFR突变型肿瘤对免疫治疗的响应，获得增效的新免疫联合治疗策略，可以丰富EGFR突变型晚期NSCLC患者在靶向治疗耐药后的临床治疗选择，进一步改善此类患者的生存预后。该文就EGFR突变型晚期NSCLC免疫治疗的最新临床研究进展、不同EGFR突变型免疫治疗效果差异、EGFR突变型NSCLC免疫联合治疗的增敏机制和潜在联合治疗方案进行综述。
黄华艳 , 徐张闻笛 , 夏立亮 , 虞永峰 , 陆舜 . 表皮生长因子受体突变型晚期非小细胞肺癌免疫治疗的研究进展[J]. 上海交通大学学报（医学版）, 2023 , 43(5) : 611 -618 . DOI: 10.3969/j.issn.1674-8115.2023.05.012
The incidence of epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancer (NSCLC) in Asians is significantly higher than that in Westerners. For the past few years, immune checkpoint inhibitors (ICIs) that target the programmed cell death 1 (PD-1) /programmed cell death ligand 1 (PD-L1) axis have become a part of the treatment paradigm for advanced NSCLC, opening a new era of immunotherapy for lung cancer. However, previous clinical trials reported that advanced NSCLC patients with EGFR mutation could not benefit from ICIs monotherapy. The immunotherapy outcomes of different EGFR mutant subtypes showed diverse. The interim results of the latest clinical trial ORIENT-31 showed that immunotherapy combined with chemotherapy and anti-angiogenesis significantly improved the progression-free survival of EGFR tyrosine kinase inhibitors (TKIs) resistant advanced NSCLC patients, providing a new therapeutic strategy for those EGFR mutant patients. The tumor microenvironment of EGFR-mutated NSCLC is immunosuppressed. Targeting the key immunomodulatory factors that play important roles in the immunosuppression may promote the response of EGFR-mutated tumors to immunotherapy and provide a new synergistic immune combination therapy strategy, which will enrich the clinical treatment options and improve the survival prognosis of EGFR-TKIs-resistant NSCLC patients. This article summarizes the latest clinical progression of immunotherapy in advanced NSCLC with EGFR mutation, the differences of immunotherapy efficacy among different EGFR mutation subtypes, the synergistic mechanism of combined immunotherapy and the potential molecular target combining with immunotherapy in EGFR-mutated NSCLC.
| 1 | SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249. |
| 2 | ZHENG R S, ZHANG S W, ZENG H M, et al. Cancer incidence and mortality in China, 2016[J]. J Natl Cancer Cent, 2022, 2(1): 1-9. |
| 3 | MOLINA J R, YANG P, CASSIVI S D, et al. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship[J]. Mayo Clin Proc, 2008, 83(5): 584-594. |
| 4 | SHI Y K, AU J S K, THONGPRASERT S, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER)[J]. J Thorac Oncol, 2014, 9(2): 154-162. |
| 5 | SHARMA S V, BELL D W, SETTLEMAN J, et al. Epidermal growth factor receptor mutations in lung cancer[J]. Nat Rev Cancer, 2007, 7(3): 169-181. |
| 6 | SORIA J C, OHE Y, VANSTEENKISTE J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer[J]. N Engl J Med, 2018, 378(2): 113-125. |
| 7 | ETTINGER D S, WOOD D E, AISNER D L, et al. Non-small cell lung cancer, version 3.2022, NCCN clinical practice guidelines in oncology[J]. J Natl Compr Canc Netw, 2022, 20(5): 497-530. |
| 8 | OHASHI K, MARUVKA Y E, MICHOR F, et al. Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease[J]. J Clin Oncol, 2013, 31(8): 1070-1080. |
| 9 | GARON E B, HELLMANN M D, RIZVI N A, et al. Five-year overall survival for patients with advanced non-small-cell lung cancer treated with pembrolizumab: results from the phase Ⅰ KEYNOTE-001 study[J]. J Clin Oncol, 2019, 37(28): 2518-2527. |
| 10 | AKBAY E A, KOYAMA S, CARRETERO J, et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors[J]. Cancer Discov, 2013, 3(12): 1355-1363. |
| 11 | LEE C K, MAN J, LORD S, et al. Checkpoint inhibitors in metastatic EGFR-mutated non-small cell lung cancer: a meta-analysis[J]. J Thorac Oncol, 2017, 12(2): 403-407. |
| 12 | HASTINGS K, YU H A, WEI W, et al. EGFR mutation subtypes and response to immune checkpoint blockade treatment in non-small-cell lung cancer[J]. Ann Oncol, 2019, 30(8): 1311-1320. |
| 13 | NOGAMI N, BARLESI F, SOCINSKI M A, et al. IMpower150 final exploratory analyses for atezolizumab plus bevacizumab and chemotherapy in key NSCLC patient subgroups with EGFR mutations or metastases in the liver or brain[J]. J Thorac Oncol, 2022, 17(2): 309-323. |
| 14 | LU S, WU L, JIAN H, et al. Sintilimab plus bevacizumab biosimilar IBI305 and chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): first interim results from a randomised, double-blind, multicentre, phase 3 trial[J]. Lancet Oncol, 2022, 23(9): 1167-1179. |
| 15 | 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. |
| 16 | LISBERG A, CUMMINGS A, GOLDMAN J W, et al. A phase Ⅱ study of pembrolizumab in EGFR-mutant, PD-L1+, tyrosine kinase inhibitor na?ve patients with advanced NSCLC[J]. J Thorac Oncol, 2018, 13(8): 1138-1145. |
| 17 | GARON E B, Wolf B, LISBERG A, et al. Prior TKI therapy in NSCLC EGFR mutant patients associates with lack of response to anti-PD-1 treatment[J]. J Thorac Oncol, 2015, 10(9 Suppl 2): S269. |
| 18 | GETTINGER S, RIZVI N A, CHOW L Q, et al. Nivolumab monotherapy for first-line treatment of advanced non-small-cell lung cancer[J]. J Clin Oncol, 2016, 34(25): 2980-2987. |
| 19 | PETERS S, GETTINGER S, JOHNSON M L, et al. Phase Ⅱ trial of atezolizumab as first-line or subsequent therapy for patients with programmed death-ligand 1-selected advanced non-small-cell lung cancer (BIRCH)[J]. J Clin Oncol, 2017, 35(24): 2781-2789. |
| 20 | RITTMEYER A, BARLESI F, WATERKAMP D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial[J]. Lancet, 2017, 389(10066): 255-265. |
| 21 | BORGHAEI H, PAZ-ARES L, HORN L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer[J]. N Engl J Med, 2015, 373(17): 1627-1639. |
| 22 | GARASSINO M C, CHO B C, KIM J H, et al. Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study[J]. Lancet Oncol, 2018, 19(4): 521-536. |
| 23 | 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. |
| 24 | HAYASHI H, SUGAWARA S, FUKUDA Y, et al. A randomized phase Ⅱ study comparing nivolumab with carboplatin-pemetrexed for EGFR-mutated NSCLC with resistance to EGFR tyrosine kinase inhibitors (WJOG8515L)[J]. Clin Cancer Res, 2022, 28(5): 893-902. |
| 25 | AREDO J V, MAMBETSARIEV I, HELLYER J A, et al. Durvalumab for stage Ⅲ EGFR-mutated NSCLC after definitive chemoradiotherapy[J]. J Thorac Oncol, 2021, 16(6): 1030-1041. |
| 26 | HELLMANN M D, PAZ-ARES L, CARO R B, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer[J]. N Engl J Med, 2019, 381(21): 2020-2031. |
| 27 | HELLMANN M D, RIZVI N A, GOLDMAN J W, et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study[J]. Lancet Oncol, 2017, 18(1): 31-41. |
| 28 | GUBENS M A, SEQUIST L V, STEVENSON J P, et al. Pembrolizumab in combination with ipilimumab as second-line or later therapy for advanced non-small-cell lung cancer: KEYNOTE-021 cohorts D and H[J]. Lung Cancer, 2019, 130: 59-66. |
| 29 | SUGIYAMA E, TOGASHI Y, TAKEUCHI Y, et al. Blockade of EGFR improves responsiveness to PD-1 blockade in EGFR-mutated non-small cell lung cancer[J]. Sci Immunol, 2020, 5(43): eaav3937. |
| 30 | YANG J C, GADGEEL S M, SEQUIST L V, et al. Pembrolizumab in combination with erlotinib or gefitinib as first-line therapy for advanced NSCLC with sensitizing EGFR mutation[J]. J Thorac Oncol, 2019, 14(3): 553-559. |
| 31 | CREELAN B C, YEH T C, KIM S W, et al. A Phase 1 study of gefitinib combined with durvalumab in EGFR TKI-naive patients with EGFR mutation-positive locally advanced/metastatic non-small-cell lung cancer[J]. Br J Cancer, 2021, 124(2): 383-390. |
| 32 | GETTINGER S, HELLMANN M D, CHOW L Q M, et al. Nivolumab plus erlotinib in patients with EGFR-mutant advanced NSCLC[J]. J Thorac Oncol, 2018, 13(9): 1363-1372. |
| 33 | OXNARD G R, YU H, et al. TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer[J]. Ann Oncol, 2020, 31(4): 507-516. |
| 34 | YANG J C H, SHEPHERD F A, KIM D W, et al. Osimertinib plus durvalumab versus osimertinib monotherapy in EGFR T790M-positive NSCLC following previous EGFR TKI therapy: CAURAL brief report[J]. J Thorac Oncol, 2019, 14(5): 933-939. |
| 35 | SCHOENFELD A J, ARBOUR K C, RIZVI H, et al. Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib[J]. Ann Oncol, 2019, 30(5): 839-844. |
| 36 | RIZVI N A, HELLMANN M D, BRAHMER J R, et al. Nivolumab in combination with platinum-based doublet chemotherapy for first-line treatment of advanced non-small-cell lung cancer[J]. J Clin Oncol, 2016, 34(25): 2969-2979. |
| 37 | SHEN C A, CHAO H S, SHIAO T H, et al. Comparison of the outcome between immunotherapy alone or in combination with chemotherapy in EGFR-mutant non-small cell lung cancer[J]. Sci Rep, 2021, 11: 16122. |
| 38 | LIU S T, WU F Y, LI X F, 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. |
| 39 | LU S, WU L, JIAN H, et al. Sintilimab with or without IBI305 plus chemotherapy in patients with EGFR mutated non-squamous non-small cell lung cancer (EGFRm nsqNSCLC) who progressed on EGFR tyrosine-kinase inhibitors (TKIs) therapy: second interim analysis of phase Ⅲ ORIENT-31 study[J]. Ann Oncol, 2022, 33: S1424. |
| 40 | LAM T C, TSANG K C, CHOI H C, et al. Combination atezolizumab, bevacizumab, pemetrexed and carboplatin for metastatic EGFR mutated NSCLC after TKI failure[J]. Lung Cancer, 2021, 159: 18-26. |
| 41 | ROBICHAUX J P, LE X N, VIJAYAN R S K, et al. Structure-based classification predicts drug response in EGFR-mutant NSCLC[J]. Nature, 2021, 597(7878): 732-737. |
| 42 | CHEN Y, YANG Z Y, WANG Y N, et al. Pembrolizumab plus chemotherapy or anlotinib vs. pembrolizumab alone in patients with previously treated EGFR-mutant NSCLC[J]. Front Oncol, 2021, 11: 671228. |
| 43 | TIAN T, YU M, LI J, et al. Front-line ICI-based combination therapy post-TKI resistance may improve survival in NSCLC patients with EGFR mutation[J]. Front Oncol, 2021, 11: 739090. |
| 44 | CHEN Q, SHANG X L, LIU N, et al. Features of patients with advanced EGFR-mutated non-small cell lung cancer benefiting from immune checkpoint inhibitors[J]. Front Immunol, 2022, 13: 931718. |
| 45 | YU H A, ARCILA M E, REKHTMAN N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers[J]. Clin Cancer Res, 2013, 19(8): 2240-2247. |
| 46 | 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. |
| 47 | YU X, LI J Q, YE L Y, et al. Real-world outcomes of chemo-antiangiogenesis versus chemo-immunotherapy combinations in EGFR-mutant advanced non-small cell lung cancer patients after failure of EGFR-TKI therapy[J]. Transl Lung Cancer Res, 2021, 10(9): 3782-3792. |
| 48 | HARATANI K, HAYASHI H, TANAKA T, et al. Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment[J]. Ann Oncol, 2017, 28(7): 1532-1539. |
| 49 | OU S H I, LIN H M, HONG J L, et al. Real-world response and outcomes in NSCLC patients with EGFR exon 20 insertion mutations[J]. J Clin Oncol, 2021, 39(15_suppl): 9098. |
| 50 | YANG G J, YANG Y N, LIU R Z, et al. First-line immunotherapy or angiogenesis inhibitor combined with chemotherapy for advanced non-small cell lung cancer with EGFR exon 20 insertions: real-world evidence from China[J]. Cancer Med, 2023, 12(1): 335-344. |
| 51 | HUNG M S, CHEN I C, LIN P Y, et al. Epidermal growth factor receptor mutation enhances expression of vascular endothelial growth factor in lung cancer[J]. Oncol Lett, 2016, 12(6): 4598-4604. |
| 52 | CHEN D S, HURWITZ H. Combinations of bevacizumab with cancer immunotherapy[J]. Cancer J, 2018, 24(4): 193-204. |
| 53 | BORGSTR?M P, HUGHES G K, HANSELL P, et al. Leukocyte adhesion in angiogenic blood vessels. Role of E-selectin, P-selectin, and β2 integrin in lymphotoxin-mediated leukocyte recruitment in tumor microvessels[J]. J Clin Invest, 1997, 99(9): 2246-2253. |
| 54 | WALLIN J J, BENDELL J C, FUNKE R, et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma[J]. Nat Commun, 2016, 7: 12624. |
| 55 | HUANG Y H, YUAN J P, RIGHI E, et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy[J]. Proc Natl Acad Sci U S A, 2012, 109(43): 17561-17566. |
| 56 | VORON T, COLUSSI O, MARCHETEAU E, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors[J]. J Exp Med, 2015, 212(2): 139-148. |
| 57 | STAGG J, DIVISEKERA U, DURET H, et al. CD73-deficient mice have increased antitumor immunity and are resistant to experimental metastasis[J]. Cancer Res, 2011, 71(8): 2892-2900. |
| 58 | STAGG J, BEAVIS P A, DIVISEKERA U, et al. CD73-deficient mice are resistant to carcinogenesis[J]. Cancer Res, 2012, 72(9): 2190-2196. |
| 59 | VIGANO S, ALATZOGLOU D, IRVING M, et al. Targeting adenosine in cancer immunotherapy to enhance T-cell function[J]. Front Immunol, 2019, 10: 925. |
| 60 | LE X N, 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. |
| 61 | TU E, MCGLINCHEY K, WANG J X, et al. Anti-PD-L1 and anti-CD73 combination therapy promotes T cell response to EGFR-mutated NSCLC[J]. JCI Insight, 2022, 7(3): e142843. |
| 62 | LIANG S Y, RISTICH V, ARASE H, et al. Modulation of dendritic cell differentiation by HLA-G and ILT4 requires the IL-6: STAT3 signaling pathway[J]. Proc Natl Acad Sci U S A, 2008, 105(24): 8357-8362. |
| 63 | GAO A Q, SUN Y P, PENG G Y. ILT4 functions as a potential checkpoint molecule for tumor immunotherapy[J]. Biochim Biophys Acta Rev Cancer, 2018, 1869(2): 278-285. |
| 64 | CHEN X Z, GAO A Q, ZHANG F, et al. ILT4 inhibition prevents TAM- and dysfunctional T cell-mediated immunosuppression and enhances the efficacy of anti-PD-L1 therapy in NSCLC with EGFR activation[J]. Theranostics, 2021, 11(7): 3392-3416. |
| 65 | BATLLE E, MASSAGUé J. Transforming growth factor-β signaling in immunity and cancer[J]. Immunity, 2019, 50(4): 924-940. |
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