Research Progress of Immune Checkpoint Inhibitors Combined with Anti-Angiogenic Drugs in Treatment of Advanced Non-Small Cell Lung Cancer
-
摘要:
免疫检查点抑制剂（ICIs）的应用改善了晚期非小细胞肺癌（NSCLC）患者的预后。然而，仍有部分患者未能从中获益。近年来，研究证明抗血管生成药与ICIs联合可增强抗肿瘤效应，国内外指南中也建议晚期NSCLC患者可采用ICIs联合抗血管治疗方案。因此，本文就ICIs与抗血管生成药物联合治疗晚期NSCLC的作用机制和最新临床研究进行综述，以期为晚期NSCLC的治疗提供参考。
Abstract:The use of immune checkpoint inhibitors (ICIs) improves the prognosis of patients with advanced non-small cell lung cancer (NSCLC). However, some patients still fail to benefit from them. In recent years, studies have demonstrated that the combination of antiangiogenic agents with ICIs can enhance the antitumor effect, and guidelines at home and abroad have suggested that the combination of ICIs with antiangiogenic regimens can be used in patients with advanced NSCLC. Therefore, the mechanism of action and the latest clinical studies on the combination of ICIs and anti-angiogenic drugs in the treatment of advanced NSCLC were reviewed in this article to provide reference for treating advanced NSCLC.
-
Competing interests: The authors declare that they have no competing interests.利益冲突声明：所有作者均声明不存在利益冲突。作者贡献：曾爱菊：文献查阅，文章撰写马代远：文章修改
-
表 1 ICIs联合抗血管生成药治疗晚期NSCLC的临床研究
Table 1 Clinical study of ICIs combined with anti-angiogenic drugs for advanced NSCLC
Study Patient Research program Sample size Primary endpoint Result IMpower150 (Phase 3)[24] Stage Ⅳ non-squamous NSCLC ABCP: Atezolizumab + bevacizumab + platinum-based doublet chemotherapy
ACP: Atezolizumab + platinum-based doublet chemotherapy
BCP: Bevacizumab + platinum-based doublet chemotherapy1202 PFS
OSABCP vs. BCP
mPFS: 8.3 vs. 6.8 m (IIT-WT)
mPFS: 11.3 vs. 6.8 m (Teff-High WT)
mOS: 19.2 vs. 14.7 m (Teff-High WT)ENPOWER (Phase 2)[25] Stage Ⅳ EGFR/ ALK-negative non-squamous NSCLC Queue 1: rh-Endostatin + PD-1 + platinum-based doublet chemotherapy
Queue 2: rh-Endostatin + platinum-based doublet chemotherapy50 ORR
PFSQueue 1 vs. Queue 2
ORR: 57.7% vs. 34.2%
mPFS: 16.7 vs. 16.4 mLEAP007
(Phase 3)[26]Stage Ⅳ EGFR/ ALK-negative NSCLC Trial group: Lenvatinib + Pembrolizumab
Control group: Placebo + pembrolizumab623 PFS
OSTrial vs. Control group
mPFS: 6.6 vs. 4.2 m
mOS: 16.4 vs. 14.1 m
(P=0.79744 )IMpower151 (Phase 3)[27] Stage Ⅳ non-squamous NSCLC ABCP: Atezolizumab + bevacizumab + platinum-based doublet chemotherapy
BCP: Placebo + bevacizumab + platinum-based doublet chemotherapy305 PFS ABCP vs. BCP
mPFS: 9.5 vs. 7.1 m
(P=0.1838 )ORIENT-31 (Phase 3)[28] Stage Ⅲ/Ⅳ EGFR mutant non-squamous NSCLC Sintilimab + bevacizumab bio-drugs + chemotherapy
bevacizumab bio-drugs+ chemotherapy
chemotherapy1011 PFS Four medicines vs. Chemotherapy group
mPFS: 7.2 vs. 4.3 m
mOS: 21.1 vs. 19.2 m
下载: 导出CSV
表 2 免疫检查点抑制剂联合抗血管生成药物治疗NSCLC的部分前瞻性研究
Table 2 Some prospective studies of immune checkpoint inhibitors combined with antiangiogenic agents in treatment of NSCLC
Study Study staging Patient Research program Primary endpoint NCT05184712
(HARMONi-A)[45]Phase 3 Stage ⅢB/Ⅳ NSCLC with disease progression after treatment with EGFR-TKI Experimental group: Ivonescimab + platinum-based doublet chemotherapy Control group: Placebo + platinum-based doublet chemotherapy PFS NCT05756972[46] Monobrachial
stage ⅡStage ⅢB/Ⅳ NSCLC with disease progression after treatment with EGFR-TKI PM8002 Combined pemetrexed and carboplatin ORR and PFS NCT03377023① Phase Ⅰ/Ⅱ Stage Ⅳ NSCLC Nivolumab + ipilimumab + nintedanib Maximum tolerated dose and ORR NCT02681549[47] Phase 2 Brain metastatic melanoma or NSCLC Pembrolizumab + bevacizumab BMS response rates using modified RECIST criteria NCT05972460② Phase Ⅰa Advanced solid tumor IMM2510 dose escalation via intravesical administration every two weeks until 52 weeks AE Notes: ①: registered on Clinical Trail website, currently closed to recruitment, no study results yet published; ②: registered on Clinical Trail website, currently recruiting patients.
下载: 导出CSV
-
[1] Sung H, Ferlay J, Siegel RL, 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. doi: 10.3322/caac.21660
[2] Chen P, Liu Y, Wen Y, et al. Non-small cell lung cancer in China[J]. Cancer Commun(Lond), 2022, 42(10): 937-970.
[3] 李岚, 许斌, 武杰, 等. 原发灶手术对Ⅳ期非小细胞肺癌患者生存的影响[J]. 中华肿瘤杂志, 2021, 43(3): 335-344. [Li L, Xu B, Wu J, et al. Survival benefit of primary site surgery acquired by stage Ⅳ non-small cell lung cancer: a retrospective study based on seer database[J]. Zhonghua Zhong Liu Za Zhi, 2021, 43(3): 335-344.] doi: 10.3760/cma.j.cn112152-20190123-00035 Li L, Xu B, Wu J, et al. Survival benefit of primary site surgery acquired by stage Ⅳ non-small cell lung cancer: a retrospective study based on seer database[J]. Zhonghua Zhong Liu Za Zhi, 2021, 43(3): 335-344. doi: 10.3760/cma.j.cn112152-20190123-00035
[4] Meador CB, Hata AN. Acquired resistance to targeted therapies in NSCLC: Updates and evolving insights[J]. Pharmacol Ther, 2020, 210: 107522. doi: 10.1016/j.pharmthera.2020.107522
[5] Lefler DS, Manobianco SA, Bashir B. Immunotherapy resistance in solid tumors: mechanisms and potential solutions[J]. Cancer Biol Ther, 2024, 25(1): 2315655. doi: 10.1080/15384047.2024.2315655
[6] Li A, Fang J. Anti-angiogenic therapy enhances cancer immunotherapy: Mechanism and clinical application[J]. Interdiscip Med, 2024, 2(1): e20230025.
[7] Aguiar RBD, Moraes JZD. Exploring the Immunological Mechanisms Underlying the Anti-vascular Endothelial Growth Factor Activity in Tumors[J]. Front Immunol, 2019, 10: 1023. doi: 10.3389/fimmu.2019.01023
[8] Ren S, Xiong X, You H, et al. The Combination of Immune Checkpoint Blockade and Angiogenesis Inhibitors in the Treatment of Advanced Non-Small Cell Lung Cancer[J]. Front Immunol, 2021, 12: 689132.
[9] Lugano R, Ramachandran M, Dimberg A. Tumor angiogenesis: causes, consequences, challenges and opportunities[J]. Cell Mol Life Sci, 2020, 77(9): 1745-1770.
[10] He D, Wang L, Xu J, et al. Research advances in mechanism of antiangiogenic therapy combined with immune checkpoint inhibitors for treatment of non-small cell lung cancer[J]. Front Immunol, 2023, 14: 1265865. doi: 10.3389/fimmu.2023.1265865
[11] Fukumura D, Kloepper J, Amoozgar Z, et al. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges[J]. Nat Rev Clin Oncol, 2018, 15(5): 325-340.
[12] Zhang W, Wang M, Ji C, et al. Macrophage polarization in the tumor microenvironment: Emerging roles and therapeutic potentials[J]. Biomed Pharmacother, 2024, 177: 116930.
[13] Dings RPM, Vang KB, Castermans K, et al. Enhancement of T-cell–Mediated Antitumor Response: Angiostatic Adjuvant to Immunotherapy against Cancer[J]. Clin Cancer Res, 2011, 17(10): 3134-3145.
[14] Heist RS, Duda DG, Sahani DV, et al. Improved tumor vascularization after anti-VEGF therapy with carboplatin and nab-paclitaxel associates with survival in lung cancer[J]. Proc Natl Acad Sci U S A, 2015, 112(5): 1547-1552.
[15] Lee WS, Yang H, Chon HJ, et al. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity[J]. Exp Mol Med, 2020, 52(9): 1475-1485.
[16] Tian L, Goldstein A, Wang H, et al. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming[J]. Nature, 2017, 544(7649): 250-254.
[17] Huang Y, Yuan J, 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.
[18] Du Four S, Maenhout SK, Niclou SP, et al. Combined VEGFR and CTLA-4 blockade increases the antigen-presenting function of intratumoral DCs and reduces the suppressive capacity of intratumoral MDSCs[J]. Am J Cancer Res, 2016, 6(11): 2514-2531.
[19] Zhao S, Ren S, Jiang T, et al. Low-Dose Apatinib Optimizes Tumor Microenvironment and Potentiates Antitumor Effect of PD-1/PD-L1 Blockade in Lung Cancer[J]. Cancer Immunol Res, 2019, 7(4): 630-643.
[20] Jing X, Yang F, Shao C, et al. Role of hypoxia in cancer therapy by regulating the tumor microenvironment[J]. Mol Cancer, 2019, 18(1): 157.
[21] Qian B, Pollard JW. Macrophage Diversity Enhances Tumor Progression and Metastasis[J]. Cell, 2010, 141(1): 39-51.
[22] Zhang Y, Zhang Z. The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications[J]. Cell Mol Immunol, 2020, 17(8): 807-821.
[23] Zheng X, Fang Z, Liu X, et al. Increased vessel perfusion predicts the efficacy of immune checkpoint blockade[J]. J Clin Invest, 2018, 128(5): 2104-2115.
[24] Nogami N, Barlesi F, Socinski MA, 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.
[25] Wang D, Feng Y, Wang H, et al. EP11.02-09 Rh-endostatin Combined With PD-1 inhibitors as First-line Treatment for EGFR/ALK-Negative, Non-squamous NSCLC[J]. J Thorac Oncol, 2023, 18(11_Suppl): S618.
[26] Yang JC, Han B, De La Mora Jiménez E, et al. Pembrolizumab With or Without Lenvatinib for First-Line Metastatic NSCLC With Programmed Cell Death-Ligand 1 Tumor Proportion Score of at least 1% (LEAP-007): A Randomized, Double-Blind, Phase 3 Trial[J]. J Thorac Oncol, 2024, 19(6): 941-953.
[27] Zhou C, Dong X, Chen G, et al. OA09.06 IMpower151: Phase Ⅲ Study of Atezolizumab + Bevacizumab + Chemotherapy in 1L Metastatic Nonsquamous NSCLC[J]. J Thorac Oncol, 2023, 18(11_Suppl): S64-S65.
[28] Lu S, Wu L, Jian H, et al. Sintilimab plus chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer with disease progression after EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): second interim analysis from a double-blind, randomised, placebo-controlled, phase 3 trial[J]. Lancet Respir Med, 2023, 11(7): 624-636.
[29] Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC[J]. N Engl J Med, 2018, 378(24): 2288-2301.
[30] Lee J, Koh J, Kim HK, et al. Bevacizumab Plus Atezolizumab After Progression on Atezolizumab Monotherapy in Pretreated Patients With NSCLC: An Open-Label, Two-Stage, Phase 2 Trial[J]. J Thorac Oncol, 2022, 17(7): 900-908.
[31] Seto T, Nosaki K, Shimokawa M, et al. Phase Ⅱ study of atezolizumab with bevacizumab for non-squamous non-small cell lung cancer with high PD-L1 expression (@Be Study)[J]. J Immunother Cancer, 2022, 10(2): e004025. doi: 10.1136/jitc-2021-004025
[32] Provencio M, Ortega AL, Coves-Sarto J, et al. Atezolizumab Plus Bevacizumab as First-line Treatment for Patients With Metastatic Nonsquamous Non–Small Cell Lung Cancer With High Tumor Mutation Burden: A Nonrandomized Controlled Trial[J]. JAMA Oncol, 2023, 9(3): 344-353. doi: 10.1001/jamaoncol.2022.5959
[33] Chu T, Zhong R, Zhong H, et al. Phase 1b Study of Sintilimab Plus Anlotinib as First-line Therapy in Patients With Advanced NSCLC[J]. J Thorac Oncol, 2021, 16(4): 643-652. doi: 10.1016/j.jtho.2020.11.026
[34] Tang JW, Qian X, Luo J, et al. 80P Efficacy and safety of tislelizumab combined with anlotinib and 2-cycles chemotherapy as first-line treatment for advanced NSCLC (TISAL-FE-01)[J]. IOTCH, 2023, 20(Suppl): 100552.
[35] Yu L, Xu J, Qiao R, et al. Comparative efficacy and safety of multitarget angiogenesis inhibitor combined with immune checkpoint inhibitor and nivolumab monotherapy as second-line or beyond for advanced lung adenocarcinoma in driver-negative patients: a retrospective comparative cohort study[J]. Transl Lung Cancer Res, 2023, 12(5): 1108-1121. doi: 10.21037/tlcr-23-260
[36] Herbst RS, Cho BC, Zhou C, et al. 64O Lenvatinib plus pembrolizumab, pemetrexed, and a platinum (len + pembro + chemo) as first-line therapy for metastatic non squamous non-small cell lung cancer (NSCLC): Phase Ⅲ LEAP-006 study[J]. IOTCH, 2023, 20(Suppl): 100536.
[37] Leighl N, Paz-Ares L, Abreu DR, et al. 65O Phase Ⅲ LEAP-008 study of lenvatinib plus pembrolizumab versus docetaxel for metastatic non-small cell lung cancer (NSCLC) that progressed on a PD-(L)1 inhibitor and platinum-containing chemotherapy[J]. IOTCH, 2023, 20(Suppl): 100537.
[38] Neal J, Pavlakis N, Kim SW, et al. CONTACT-01: A Randomized Phase Ⅲ Trial of Atezolizumab + Cabozantinib Versus Docetaxel for Metastatic Non-Small Cell Lung Cancer After a Checkpoint Inhibitor and Chemotherapy[J]. J Clin Oncol, 2024, 42(20): 2393-2403. doi: 10.1200/JCO.23.02166
[39] Wu L, Pu X, Chen B, et al. P40.14 Efficacy and Safety of Endostar Combined With Camrelizumab and Chemotherapy in Treatment of Advanced NSCLC: A Multi-Center Retrospective Study[J]. J Thorac Oncol, 2021, 16(10_ Suppl): S1075-S1076.
[40] Yuan S, Miao C. 70P Phase Ⅱ clinical study of envafolimab combined with recombinant human endostatin and chemotherapy as a first-line treatment for driver gene-negative advanced non-small cell lung cancer[J]. ESMO Open, 2024, 9: 102649.
[41] Watanabe S, Furuya N, Nakamura A, et al. A phase Ⅱ study of atezolizumab with bevacizumab, carboplatin, and paclitaxel for patients with EGFR-mutated NSCLC after TKI treatment failure (NEJ043 study)[J]. Eur J Cancer, 2024, 197: 113469.
[42] Park S, Kim TM, Han JY, et al. Phase Ⅲ, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Rearranged or Translocated Non–Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04)[J]. J Clin Oncol, 2024, 42(11): 1241-1251.
[43] Shiraishi Y, Kishimoto J, Sugawara S, et al. Atezolizumab and Platinum Plus Pemetrexed With or Without Bevacizumab for Metastatic Nonsquamous Non–Small Cell Lung Cancer: A Phase 3 Randomized Clinical Trial[J]. JAMA Oncol, 2024, 10(3): 315-324.
[44] Shi M, Chen P, Cui B, et al. Benmelstobart plus anlotinib in patients with EGFR-positive advanced NSCLC after failure of EGFR TKIs therapy: a phase Ⅰ/Ⅱ study[J]. Signal Transduct Target Ther, 2024, 9(1): 283. doi: 10.1038/s41392-024-01982-2
[45] Harmoni-A Study Investigators, Fang W, Zhao Y, et al. Ivonescimab Plus Chemotherapy in Non–Small Cell Lung Cancer With EGFR Variant: A Randomized Clinical Trial[J]. JAMA, 2024, 332(7): 561-570.
[46] Wu Y L, Wang Z, Cheng Y, et al. 1255MO A phase Ⅱ safety and efficacy study of PM8002/BNT327 in combination with chemotherapy in patients with EGFR-mutated non-small cell lung cancer (NSCLC)[J]. Ann Oncol, 2024, 35(Suppl_2): S804.
[47] Weiss SA, Djureinovic D, Wei W, et al. Phase Ⅱ Trial of Pembrolizumab in Combination With Bevacizumab for Untreated Melanoma Brain Metastases[J]. J Clin Oncol, 2025, JCO-24-02219. Online ahead of print.
