Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Medicine
Published in: BMC Medicine 1/2024

Open Access 01-12-2024 | Osimertinib | Research article

Osimertinib in combination with anti-angiogenesis therapy presents a promising option for osimertinib-resistant non-small cell lung cancer

Authors: Ruoshuang Han, Haoyue Guo, Jinpeng Shi, Sha Zhao, Yijun Jia, Xiaozhen Liu, Yiwei Liu, Lei Cheng, Chao Zhao, Xuefei Li, Caicun Zhou

Published in: BMC Medicine | Issue 1/2024

Login to get access

Abstract

Background

Osimertinib has become standard care for epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) patients whereas drug resistance remains inevitable. Now we recognize that the interactions between the tumor and the tumor microenvironment (TME) also account for drug resistance. Therefore, we provide a new sight into post-osimertinib management, focusing on the alteration of TME.

Methods

We conducted a retrospective study on the prognosis of different treatments after osimertinib resistance. Next, we carried out in vivo experiment to validate our findings using a humanized mouse model. Furthermore, we performed single-cell transcriptome sequencing (scRNA-seq) of tumor tissue from the above treatment groups to explore the mechanisms of TME changes.

Results

Totally 111 advanced NSCLC patients have been enrolled in the retrospective study. The median PFS was 9.84 months (95% CI 7.0–12.6 months) in the osimertinib plus anti-angiogenesis group, significantly longer than chemotherapy (P = 0.012) and osimertinib (P = 0.003). The median OS was 16.79 months (95% CI 14.97–18.61 months) in the osimertinib plus anti-angiogenesis group, significantly better than chemotherapy (P = 0.026), the chemotherapy plus osimertinib (P = 0.021), and the chemotherapy plus immunotherapy (P = 0.006).
The efficacy of osimertinib plus anlotinib in the osimertinib-resistant engraft tumors (R-O+A) group was significantly more potent than the osimertinib (R-O) group (P<0.05) in vitro. The combinational therapy could significantly increase the infiltration of CD4+ T cells (P<0.05), CD25+CD4+ T cells (P<0.001), and PD-1+CD8+ T cells (P<0.05) compared to osimertinib.
ScRNA-seq demonstrated that the number of CD8+ T and proliferation T cells increased, and TAM.mo was downregulated in the R-O+A group compared to the R-O group. Subtype study of T cells explained that the changes caused by combination treatment were mainly related to cytotoxic T cells. Subtype study of macrophages showed that proportion and functional changes in IL-1β.mo and CCL18.mo might be responsible for rescue osimertinib resistance by combination therapy.

Conclusions

In conclusion, osimertinib plus anlotinib could improve the prognosis of patients with a progressed disease on second-line osimertinib treatment, which may ascribe to increased T cell infiltration and TAM remodeling via VEGF-VEGFR blockage.
Appendix
Available only for authorised users
Literature
1.
2.
Han B, Jin B, Chu T, Niu Y, Dong Y, Xu J, et al. Combination of chemotherapy and gefitinib as first-line treatment for patients with advanced lung adenocarcinoma and sensitive EGFR mutations: a randomized controlled trial. Int J Cancer. 2017;141(6):1249–56.PubMedCrossRef
3.
Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11(2):121–8.PubMedCrossRef
4.
Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med. 2017;376(7):629–40.PubMedCrossRef
5.
Le X, Puri S, Negrao MV, Nilsson MB, Robichaux J, Boyle T, et al. Landscape of EGFR-Dependent and -Independent Resistance Mechanisms to Osimertinib and Continuation Therapy Beyond Progression in EGFR-Mutant NSCLC. Clin Cancer Res. 2018;24(24):6195–203.PubMedPubMedCentralCrossRef
6.
Leonetti A, Sharma S, Minari R, Perego P, Giovannetti E, Tiseo M. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer. 2019;121(9):725–37.PubMedPubMedCentralCrossRef
7.
Wang Y, Li L, Han R, Jiao L, Zheng J, He Y. Clinical analysis by next-generation sequencing for NSCLC patients with MET amplification resistant to osimertinib. Lung Cancer. 2018;118:105–10.PubMedCrossRef
8.
Remon J, Steuer CE, Ramalingam SS, Felip E. Osimertinib and other third-generation EGFR TKI in EGFR-mutant NSCLC patients. Ann Oncol. 2018;29(suppl_1):i20–7.PubMedCrossRef
9.
Oxnard GR, Hu Y, Mileham KF, Husain H, Costa DB, Tracy P, et al. Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib. JAMA Oncol. 2018;4(11):1527–34.PubMedCrossRef
10.
Di Noia V, D’Aveni A, D’Argento E, Rossi S, Ghirardelli P, Bortolotti L, et al. Treating disease progression with osimertinib in EGFR-mutated non-small-cell lung cancer: novel targeted agents and combination strategies. ESMO Open. 2021;6(6):100280.PubMedPubMedCentralCrossRef
11.
Schmid S, Li JJN, Leighl NB. Mechanisms of osimertinib resistance and emerging treatment options. Lung Cancer. 2020;147:123–9.PubMedCrossRef
12.
Marcoux N, Gettinger SN, O’Kane G, Arbour KC, Neal JW, Husain H, et al. EGFR-Mutant Adenocarcinomas That Transform to Small-Cell Lung Cancer and Other Neuroendocrine Carcinomas: Clinical Outcomes. J Clin Oncol. 2019;37(4):278–85.PubMedCrossRef
13.
Tan AC, Tan DSW. Targeted therapies for lung cancer patients with oncogenic driver molecular alterations. J Clin Oncol. 2022;40(6):611–25.PubMedCrossRef
14.
Su PL, Tsai JS, Yang SC, Wu YL, Tseng YL, Chang CC, et al. Survival benefit of osimertinib combination therapy in patients with T790M-positive non-small-cell lung cancer refractory to osimertinib treatment. Lung Cancer. 2021;158:137–45.PubMedCrossRef
15.
Piotrowska Z, Liu SV, Muzikansky A, Marcoux N, Banwait M, Stevens S, et al. Safety of osimertinib plus chemotherapy in EGFR-mutant NSCLC. J Clin Oncol. 2018;36(15_suppl):e21231-e.CrossRef
16.
Neal JW, Hausrath D, Wakelee HA, Cunanan K, Liu SV, Banwait M, et al. Osimertinib with chemotherapy for EGFR-mutant NSCLC at progression: Safety profile and survival analysis. J Clin Oncol. 2019;37(15_suppl):9083.CrossRef
17.
Tian X, Gu T, Lee MH, Dong Z. Challenge and countermeasures for EGFR targeted therapy in non-small cell lung cancer. Biochim Biophys Acta Rev Cancer. 2022;1877(1):188645.PubMedCrossRef
18.
Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21(3):309–22.PubMedCrossRef
19.
Ferguson LP, Diaz E, Reya T. The role of the microenvironment and immune system in regulating stem cell fate in cancer. Trends Cancer. 2021;7(7):624–34.PubMedPubMedCentralCrossRef
20.
Mikubo M, Inoue Y, Liu G, Tsao MS. Mechanism of drug tolerant persister cancer cells: the landscape and clinical implication for therapy. J Thorac Oncol. 2021;16(11):1798–809.PubMedCrossRef
21.
Suggitt M, Bibby MC. 50 years of preclinical anticancer drug screening: empirical to target-driven approaches. Clin Cancer Res. 2005;11(3):971–81.PubMedCrossRef
22.
Ngiow SF, Loi S, Thomas D, Smyth MJ. Mouse Models of Tumor Immunotherapy. Adv Immunol. 2016;130:1–24.PubMed
23.
Zitvogel L, Pitt JM, Daillere R, Smyth MJ, Kroemer G. Mouse models in oncoimmunology. Nat Rev Cancer. 2016;16(12):759–73.PubMedCrossRef
24.
Zhou Q, Facciponte J, Jin M, Shen Q, Lin Q. Humanized NOD-SCID IL2rg-/- mice as a preclinical model for cancer research and its potential use for individualized cancer therapies. Cancer Lett. 2014;344(1):13–9.PubMedCrossRef
25.
Meraz IM, Majidi M, Meng F, Shao R, Ha MJ, Neri S, et al. An improved patient-derived xenograft humanized mouse model for evaluation of lung cancer immune responses. Cancer Immunol Res. 2019;7(8):1267–79.PubMedPubMedCentralCrossRef
26.
Lin S, Huang G, Cheng L, Li Z, Xiao Y, Deng Q, et al. Establishment of peripheral blood mononuclear cell-derived humanized lung cancer mouse models for studying efficacy of PD-L1/PD-1 targeted immunotherapy. MAbs. 2018;10(8):1301–11.PubMedPubMedCentralCrossRef
27.
Rami-Porta R, Asamura H, Travis WD, Rusch VW. Lung cancer - major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(2):138-55.
28.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.PubMedCrossRef
29.
Efremova M, Vento-Tormo M, Teichmann SA, Vento-Tormo R. Cell PhoneDB: inferring cell–cell communication from combined expression of multi-subunit ligand–receptor complexes. Nature Protocols. 2020;15(4):1484–506.PubMedCrossRef
30.
31.
Shaikh M, Shinde Y, Pawara R, Noolvi M, Surana S, Ahmad I, et al. Emerging approaches to overcome acquired drug resistance obstacles to Osimertinib in non-small-cell lung cancer. J Med Chem. 2022;65(2):1008–46.PubMedCrossRef
32.
Cheng JT, Yao YH, Gao YE, Zhang SL, Chen HJ, Wang Z, et al. Integrated histological and molecular analyses of rebiopsy samples at osimertinib progression improve post-progression survivals: a single-center retrospective study. Lung Cancer. 2020;150:97–106.PubMedCrossRef
33.
Hung MS, Chen IC, Lin PY, Lung JH, Li YC, Lin YC, et al. Epidermal growth factor receptor mutation enhances expression of vascular endothelial growth factor in lung cancer. Oncol Lett. 2016;12(6):4598–604.PubMedPubMedCentralCrossRef
34.
Naumov GN, Nilsson MB, Cascone T, Briggs A, Straume O, Akslen LA, et al. Combined vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumor growth in xenograft models of EGFR inhibitor resistance. Clin Cancer Res. 2009;15(10):3484–94.PubMedPubMedCentralCrossRef
35.
Nakagawa K, Garon EB, Seto T, Nishio M, Ponce Aix S, Paz-Ares L, et al. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(12):1655–69.PubMedCrossRef
36.
Kenmotsu H, Wakuda K, Mori K, Kato T, Sugawara S, Kirita 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 Thorac Oncol. 2022;17(9):1098–108.PubMedCrossRef
37.
Soo RA, Han JY, Dafni U, Cho BC, Yeo CM, Nadal E, et al. A randomised phase II study of osimertinib and bevacizumab versus osimertinib alone as second-line targeted treatment in advanced NSCLC with confirmed EGFR and acquired T790M mutations: the European Thoracic Oncology Platform (ETOP 10–16) BOOSTER trial. Ann Oncol. 2022;33(2):181–92.PubMedCrossRef
38.
Akamatsu H, Toi Y, Hayashi H, Fujimoto D, Tachihara M, Furuya N, et al. Efficacy of Osimertinib Plus Bevacizumab vs Osimertinib in Patients With EGFR T790M-Mutated Non-Small Cell Lung Cancer Previously Treated With Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor: West Japan Oncology Group 8715L Phase 2 Randomized Clinical Trial. JAMA Oncol. 2021;7(3):386–94.PubMedPubMedCentralCrossRef
39.
Daum S, Hagen H, Naismith E, Wolf D, Pircher A. The role of anti-angiogenesis in the treatment landscape of non-small cell lung cancer - new combinational approaches and strategies of neovessel inhibition. Front Cell Dev Biol. 2020;8:610903.PubMedCrossRef
40.
Chen Y, Liu H, Hu N, Wang Y, Yang Z, Zhang J, et al. Survival benefit of anlotinib in T790M-positive non-small-cell lung cancer patients with acquired osimertinib resistance: a multicenter retrospective study and exploratory in vitro study. Cancer Med. 2023;12(15):15922–32.PubMedPubMedCentralCrossRef
41.
42.
Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis. Cell. 2011;146(6):873–87.PubMedCrossRef
43.
44.
45.
Suda K, Bunn PA Jr, Rivard CJ, Mitsudomi T, Hirsch FR. Primary double-strike therapy for cancers to overcome egfr kinase inhibitor resistance: proposal from the bench. J Thorac Oncol. 2017;12(1):27–35.PubMedCrossRef
46.
Hegde PS, Wallin JJ, Mancao C. Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics. Semin Cancer Biol. 2018;52(Pt 2):117–24.PubMedCrossRef
47.
Huang Y, Goel S, Duda DG, Fukumura D, Jain RK. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res. 2013;73(10):2943–8.PubMedPubMedCentralCrossRef
48.
Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, Pointet AL, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med. 2015;212(2):139–48.PubMedPubMedCentralCrossRef
49.
Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med. 1996;2(10):1096–103.PubMedCrossRef
50.
Lahmar Q, Keirsse J, Laoui D, Movahedi K, Van Overmeire E, Van Ginderachter JA. Tissue-resident versus monocyte-derived macrophages in the tumor microenvironment. Biochim Biophys Acta. 2016;1865(1):23–34.PubMed
51.
52.
Müller S, Kohanbash G, Liu SJ, Alvarado B, Carrera D, Bhaduri A, et al. Single-cell profiling of human gliomas reveals macrophage ontogeny as a basis for regional differences in macrophage activation in the tumor microenvironment. Genome Biol. 2017;18(1):234.PubMedPubMedCentralCrossRef
53.
Chavez-Galan L, Olleros ML, Vesin D, Garcia I. Much more than M1 and M2 macrophages, there are also CD169(+) and TCR(+) macrophages. Front Immunol. 2015;6:263.PubMedPubMedCentral
54.
Wu Y, Yang S, Ma J, Chen Z, Song G, Rao D, et al. Spatiotemporal immune landscape of colorectal cancer liver metastasis at single-cell level. Cancer Discov. 2022;12(1):134–53.PubMedCrossRef
55.
Liu S, Zhang H, Li Y, Zhang Y, Bian Y, Zeng Y, et al. S100A4 enhances protumor macrophage polarization by control of PPAR-γ-dependent induction of fatty acid oxidation. J Immunother Cancer. 2021;9(6).
56.
Chaudhary B, Khaled YS, Ammori BJ, Elkord E. Neuropilin 1: function and therapeutic potential in cancer. Cancer Immunol Immunother. 2014;63(2):81–99.PubMedCrossRef
57.
Clear AJ, Lee AM, Calaminici M, Ramsay AG, Morris KJ, Hallam S, et al. Increased angiogenic sprouting in poor prognosis FL is associated with elevated numbers of CD163+ macrophages within the immediate sprouting microenvironment. Blood. 2010;115(24):5053–6.PubMedPubMedCentralCrossRef
58.
Hughes R, Qian BZ, Rowan C, Muthana M, Keklikoglou I, Olson OC, et al. Perivascular M2 macrophages stimulate tumor relapse after chemotherapy. Cancer Res. 2015;75(17):3479–91.PubMedPubMedCentralCrossRef
59.
Baer C, Squadrito ML, Iruela-Arispe ML, De Palma M. Reciprocal interactions between endothelial cells and macrophages in angiogenic vascular niches. Exp Cell Res. 2013;319(11):1626–34.PubMedPubMedCentralCrossRef
60.
Lewis CE, Harney AS, Pollard JW. The multifaceted role of perivascular macrophages in tumors. Cancer Cell. 2016;30(2):365.PubMedCrossRef
Metadata
Title
Osimertinib in combination with anti-angiogenesis therapy presents a promising option for osimertinib-resistant non-small cell lung cancer
Authors
Ruoshuang Han
Haoyue Guo
Jinpeng Shi
Sha Zhao
Yijun Jia
Xiaozhen Liu
Yiwei Liu
Lei Cheng
Chao Zhao
Xuefei Li
Caicun Zhou
Publication date
01-12-2024
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2024
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-024-03389-w

Other articles of this Issue 1/2024

BMC Medicine 1/2024 Go to the issue

Research article

Autoimmune diseases and adverse pregnancy outcomes: an umbrella review

Research article

Identifying the most at-risk age-group and longitudinal trends of drug allergy labeling amongst 7.3 million individuals in Hong Kong

Research article

Impact of preconception and antenatal supplementation with myo-inositol, probiotics, and micronutrients on offspring BMI and weight gain over the first 2 years

Research article

Exploration of the potential association between GLP-1 receptor agonists and suicidal or self-injurious behaviors: a pharmacovigilance study based on the FDA Adverse Event Reporting System database

Correspondence

Diagnostic and progression biomarkers in cerebrospinal fluid of Alzheimer’s disease patients

Research article

Effects of 6-month customized home-based exercise on motor development, bone strength, and parental stress in children with simple congenital heart disease: a single-blinded randomized clinical trial