International Journal of Drug Delivery Technology
Volume 15, Issue 3

Advances in Cancer Therapy: A Comprehensive Review of Fourth Generation EGFR Inhibitors and their Role in Defeating Drug Resistance

Asha Hole*, Shashikant Bhandari 

Department of Pharmaceutical Chemistry, AISSMS’s College of Pharmacy, Shivajinagar, Affiliated to Savitribai Phule Pune University, Pune, Maharashtra, India

Received: 3rd Jul, 2025; Revised: 28th Aug, 2025; Accepted: 3rd Sep, 2025; Available Online: 25th Sep, 2025 

ABSTRACT

The treatment of cancer has changed significantly as a result of the development of targeted medications, particularly inhibitors of the receptor for epidermal growth factor (EGFR), which is crucial for the development and survival of cancer. Cancers of the colorectal, head and neck, and non-small cell lung varieties often include EGFR overexpression and mutations.  The safety records, clinical effectiveness, and action mechanisms of 4thgeneration EGFR inhibitors are the primary foci of this review.  The T790M mutation is one example of a resistance mechanism that these newer, more potent inhibitors aim to counteract. In order to give patients with EGFR-mutant cancers that are resistant to earlier treatments new hope, the review outlines recent clinical developments and examines the potential applications of 4th-generation EGFR inhibitors in cancer treatment.

Keywords: EGFR inhibitors, T790M mutation, targeted therapy, cancer therapy, clinical efficacy, tumor growth

How to cite this article: Asha Hole, Shashikant Bhandari. Advances in Cancer Therapy: A Comprehensive Review of Fourth Generation EGFR Inhibitors and their Role in Defeating Drug Resistance. International Journal of Drug Delivery Technology. 2025;15(3):1406-16. doi: 10.25258/ijddt.15.3.64

REFERENCES

  1. Sobti RC, Thakur M, Kaur T. Cancer: Epidemiology, racial, and geographical disparities. In: Molecular biomarkers for cancer diagnosis and therapy. Edited by: RC Sobti, H Sugimura & A Sobti. 2024 Jun 30;(pp. 31-52). Singapore: Springer Nature Singapore. https://doi.org/10.1007/978-981-99-3746-2_3
  2. Zhong L, Li Y, Xiong L, Wang W, Wu M, Yuan T, Yang W, Tian C, Miao Z, Wang T, Yang S. Small molecules in targeted cancer therapy: advances, challenges, and future perspectives. Signal Transduction and Targeted Therapy. 2021 May 31;6(1):1-4. https://doi.org/10.1038/s41392-021-00572-w
  3. Alharbi KS, Shaikh MAJ, Afzal O, Altamimi AS, Almalki WH, Alzarea SI, Kazmi I, Al-Abbasi FA, Sinek SH, Dua K, Gupta G. An overview of epithelial growth factor receptor (EGFR) inhibitors in cancer therapy. Chemico-Biological Interactions. 2022 Oct 1;366:110108. https://doi.org/10.1016/j.cbi.2022.110108
  4. Amelia T, Kartasasmita RE, Ohwada T, Tjahjono DH. Structural insight and development of EGFR tyrosine kinase inhibitors. Molecules. 2022 Jan 26;27(3):819. https://doi.org/10.3390/molecules27030819
  5. Ramani S, Samant S, Manohar SM. The story of EGFR: from signaling pathways to a potent anticancer target. Future Medicinal Chemistry. 2022 Sep 1;14(17):1267-88. https://doi.org/10.4155/fmc-2021-0343
  6. Uribe ML, Marrocco I, Yarden Y. EGFR in cancer: signaling mechanisms, drugs, and acquired resistance. Cancers. 2021 Jun 1;13(11):2748. https://doi.org/10.3390/cancers13112748
  7. Levantini E, Maroni G, Del Re M, Tenen DG. EGFR signaling pathway as therapeutic target in human cancers. Seminars in Cancer Biology. 2022 Oct 1;85:253. https://doi.org/10.1016/j.semcancer.2022.04.002
  8. Mansour MA, AboulMagd AM, Abbas SH, Abdel-Rahman HM, Abdel-Aziz M. Insights into fourth generation selective inhibitors of (C797S) EGFR mutation combating non-small cell lung cancer resistance: a critical review. RSC Advances. 2023;13(27):18285-93. https://doi.org/10.1039/D3RA02137A
  9. Papini F, Sundaresan J, Leonetti A, Tiseo M, Rolfo C, Peters GJ, Giovannetti E. Hype or hope: can combination therapies with third-generation EGFR-TKIs help overcome acquired resistance and improve outcomes in EGFR-mutant advanced/metastatic NSCLC? Critical Reviews in Oncology/Hematology. 2021 Oct 1;166:103454. https://doi.org/10.1016/j.critrevonc.2021.103454
  10. Cheng WL, Feng PH, Lee KY, Chen KY, Sun VL, Van Hiep N, Luo CS, Wu SM. The role of EREG/EGFR pathway in tumor progression. International Journal of Molecular Sciences. 2021 Nov 27;22(23):12828. https://doi.org/10.3390/ijms222312828
  11. He Y, Sun MM, Zhang GC, Yang J, Chen KS, Xu WW, Li B. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduction and Targeted Therapy. 2021 Dec 16;6(1):425. https://doi.org/10.1038/s41392-021-00828-5
  12. Wang R. Regulation of cell cycle progression by growth factor-induced cell signaling. Cells. 2021 Nov 26;10(12):3327. https://doi.org/10.3390/cells10123327
  13. Brown BP, Zhang YK, Kim S, Finneran P, Yan Y, Du Z, Kim J, Hartzler AL, LeNoue-Newton ML, Smith AW, Meiler J, Lovely CM. Allele-specific activation, enzyme kinetics, and inhibitor sensitivities of EGFR exon 19 deletion mutations in lung cancer. Proceedings of the National Academy of Sciences of the United States of America. 2022 Jul 26;119(30):e2200585119. https://doi.org/10.1073/pnas.2200585119
  14. Turmbnik HL, Heimsoeth A, Sos ML. The next tier of EGFR resistance mutations in lung cancer. Oncogene. 2021 Jan 7;40(1):1-11. https://doi.org/10.1038/s41388-020-01551-6
  15. Dong RF, Zhu ML, Liu XM, Xu YF, Yuan L, Bian J, Xia YZ, Kong LY. EGFR mutation mediates resistance to EGFR tyrosine kinase inhibitors in NSCLC: revealing molecular mechanism to clinical research. Pharmacological Research. 2021 May 1;167:105583. https://doi.org/10.1016/j.phrs.2021.105583
  16. Wu Q, Luo W, Li W, Wang T, Huang L, Xu F. First-generation EGFR-TKI plus chemotherapy versus EGFR-TKI alone as first-line treatment in advanced NSCLC with EGFR activating mutations: a systematic review and meta-analysis of randomized controlled trials. Frontiers in Oncology. 2021 Apr 12;11:635546. https://doi.org/10.3389/fonc.2021.635546
  17. Shi K, Wang P, Shi J, Zhang J, Wang J, Duynant L, Wang Y, Li W. Emerging strategies to overcome resistance to third-generation EGFR-TKIs in advanced NSCLC. Journal of Hematology & Oncology. 2022 Jul 15;15(1):94. https://doi.org/10.1186/s13045-022-01341-5
  18. Nagasaka M, Zhu VW, Lim SM, Greco M, Wu F, Ou SI. Beyond osimertinib: the development of third-generation EGFR tyrosine kinase inhibitors for advanced NSCLC. Journal of Thoracic Oncology. 2021 May 1;16(5):740-56. https://doi.org/10.1016/j.jtho.2020.12.015
  19. Fukuda S, Suda K, Hamada A, Oiki H, Ohara S, Ito M, Soh J, Mitsudomi T, Tsutani Y. Potential utility of a 4th-generation EGFR-TKI and exploration of resistance mechanisms—an in vitro study. Biomedicines. 2024 Jun 21;12(7):1412. https://doi.org/10.3390/biomedicines12071412
  20. JP-2023532928-A. Novel macrocycles and derivatives as EGFR inhibitors. BoehringerIngelheim International GmbH. Published on Sep 14 2023. Available from: https://patents.google.com/patent/JP2023532928A/en
  21. CN-111474958-A. Novel imidazole compounds and derivatives as EGFR inhibitors. BoehringerIngelheim International GmbH. Published on Jul 31 2020. Available from: https://patents.google.com/patent/CN111474958A/en
  22. WO-2018165014-A1. Spiro-pyridyl-phosphorus-oxygen compound as fourth generation EGFR kinase inhibitor. Nanjing Medchem Pharmaceutical Co., Ltd. Published on Sep 13 2018. Available from: https://patents.google.com/patent/WO2018165014A1/en
  23. CN-113968734-A. Substituted macrocyclic compounds, compositions containing the same and uses thereof. Shenzhen Taishirui Biopharmaceutical Co., Ltd. Published on Jan 25 2022. Available from: https://patents.google.com/patent/CN113968734A/en
  24. US-20230275514-A1. Substituted 1H-pyrrolo. BoehringerIngelheim International GmbH. Published on Aug 24 2023. Available from: https://patents.google.com/patent/US20230275514A1/en
  25. KR-20220014034-A. Combination of EGFR inhibitors and ROR1 inhibitors for the treatment of cancer. Onctherapy Science, Inc. Published on Feb 11 2022. Available from: https://patents.google.com/patent/KR20220014034A/en
  26. WO-2021008850-A1. Pyrimidopyrazol compounds as fourth generation EGFR inhibitors. Jiangsu Hengrui Medicine Co., Ltd. Published on May 7 2020. Available from: https://patents.google.com/patent/WO2021008850A1/en
  27. US-11286268-B2. Fourth-generation EGFR tyrosine kinase inhibitor. Nagasaki University, Iwate Medical University, Japanese Foundation for Cancer Research. Published on Mar 29 2022. Available from: https://patents.google.com/patent/US11286268B2/en
  28. WO-2022252594-A1. EGFR inhibitor and PERK activator in combination therapy and their use for treating cancer. Qventus Life Sciences Pvt Ltd. Published on Dec 1 2022. Available from: https://patents.google.com/patent/WO2022252594A1/en
  29. Remon J, Besse B, Aix SP, Cejalvo A, Al-Naqib R, Bernabé R, Greillier L, Majem M, Reguart N, Monnet I, Cousin S, Camara P, Robinet G, Garcia Campelo R, Mazières J, Audigier-Valette C, Moro-Sibilot D, Westeel V, Baize N, Pérol M, Brosseau S, Zalcman G, Jovelet C, Girard N, Pannet C, Hollebecque A, Le Moulec S, Planchard D, Caramella C, de Baere T, Nanni L, Gazzah A, Dingemans AC, Dziadziuszko R. Osimertinib treatment beyond progression in patients (pts) with EGFR exon 20 insertion mutation non-small cell lung cancer (NSCLC): DCR cohort from the Lung Cancer Group Riga 1651 APPLE phase II randomized clinical trial. Annals of Oncology. 2023 Jan 1;34(S1):S1209-38. https://doi.org/10.1016/annonc.2023.02.012
  30. Riley GM, Jackson CM, Corridige GR, Spira AI, Piotrowska Z, Costa DB, Tsao AS, Patel JD, Gadgeel SM, Batenchuk C, Lieu JW, West HL, Mekhail T, Gernstner RD, Nguyen D, Vincent S, Zhang S, Lin J, Buon VM, Li S, Jin S, Jänne PA. Activity and safety of mobocertinib (TAK-788) in previously treated non-small cell lung cancer with EGFR exon 20 insertion mutations from a phase I/II trial. Cancer. 2021 Apr 1;127(7):1158-68. https://doi.org/10.1002/cncr.33380
  31. Tajane P, Kayande N, Bhosale A, Deore S, Tare H. Design and discovery of silmitasertib-based drugs as a potential casein kinase II inhibitor for cholangiocarcinomathrough hybrid in-silico ligand-based virtual screening with molecular docking method. Int J Drug Deliv Technol. 2023;13(4):1514-9. https://doi.org/10.25258/ijddt.13.4.60
  32. He J, Zhou Z, Sun X, Yang Z, Zheng P, Xu S, Zhu W. The new opportunities in medicinal chemistry of fourth-generation EGFR inhibitors in overcoming C797S mutation. European Journal of Medicinal Chemistry. 2021 Jan 15;210:113995. https://doi.org/10.1016/j.ejmech.2020.113995
  33. Ohe Y, Imamura S, Nogami N, Okamoto I, Kurata T, Kato T, Sugawara S, Ramalingam SS, Goto K, Hodge R, Vowler SL, Wajima T, Nishiwaki A, Nakagawa K. Osimertinib versus gefitinib as first-line treatment for EGFRm advanced NSCLC: FLAURA Japanese subset. Japanese Journal of Clinical Oncology. 2019 Jan;49(1):29-36. https://doi.org/10.1093/jjco/hyy158
  34. Papadimitrakopoulou VA, Han JY, Ahn MJ, Ramalingam SS, Delmonte A, Hsia TC, Laskin J, Kim SW, He Y, Tsai CM, Yang JC, Ohe Y, Kato T, Jenkins S, Patel S, Huang X, Lu S, Gruslova A, Threats KS, Wu YL, Mai H. Epidermal growth factor receptor mutation analysis in tissue and plasma from the AURA3 trial: osimertinib versus platinum-pemetrexed for T790M mutation-positive advanced non-small cell lung cancer. Cancer. 2020 Jan 15;126(2):373-380. https://doi.org/10.1002/cncr.32508
  35. Hanley MJ, Camidge DR, Fram RJ, Gupta N. Mobocertinib: Mechanism of action, clinical, and translational science. Clinical and Translational Science. 2024 Mar;17(3):e13766. https://doi.org/10.1111/cts.13766
  36. Markou A, Tzanikou E, Lianidou E. The potentials of liquid biopsy in the management of cancer patients. Annals of Translational Medicine. 2020 Aug;8(16):1089. https://doi.org/10.21037/atm.2020.03.194
  37. Oxnard GR, Yang JC, Yu H, Kim SW, Saka H, Horn L, et al. TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer. Ann Oncol. 2020;31(4):507-16. https://doi.org/10.1016/j.annonc.2020.01.013
  38. Lamb YN. Osimertinib: a review in previously untreated EGFR mutation-positive advanced NSCLC. Target Oncol. 2021;16(5):687-95. https://doi.org/10.1007/s11523-021-00839-w
  39. Viray H, Piper-Vallillo AJ, Widick P, Academia E, Shea M, Rangachari D, et al. Real-world study of patient characteristics and clinical outcomes in EGFR-mutated lung cancer treated with first-line osimertinib: expanding the FLAURA trial results into routine clinical practice. Cancers (Basel). 2024;16(6):1079. https://doi.org/10.3390/cancers16061079
  40. Cheng Y, He Y, Li W, Zhang HL, Zhou Q, Wang B, et al. Osimertinib versus comparator EGFR-TKI as first-line treatment for EGFR-mutated advanced NSCLC: FLAURA China. Target Oncol. 2021;16(2):165-76. https://doi.org/10.1007/s11523-021-00794-6
  41. Asahina H, Tanaka K, Morita S, Maemondo M, Seike M, Okamoto I, et al. A phase II study of osimertinib combined with platinum plus pemetrexed in patients with EGFR-mutated advanced non–small-cell lung cancer: the OPAL study (NEJ032C/LOGIK1801). Clin Lung Cancer. 2021;22(2):147-51. https://doi.org/10.1016/j.cllc.2020.09.023
  42. Arnold A, Ganti AK. Clinical utility of mobocertinib in the treatment of NSCLC—patient selection and reported outcomes. Onco Targets Ther. 2023;16:559-69. https://doi.org/10.2147/OTT.S374489
  43. Su C, Sun SY. Fourth-generation epidermal growth factor receptor-tyrosine kinase inhibitors: hope and challenges. Transl Cancer Res. 2024;13(8):3929-36. https://doi.org/10.21037/tcr-24-406
  44. Melis JU, Kevenaar K, Kooijman JJ, Grobben Y, Ytsma J, Bertran-Alamillo J, Molina-Vila MA, Willemsen-Seegers N, Zaman GJ. Abstract 4663. Characterization of fourth-generation EGFR inhibitors in binding experiments with C797S mutant EGFR and cell-based assays with osimertinib-resistant non-small cell lung cancer cell lines. Cancer Research. 2024 Mar 22;84(6_Supplement):4663. https://doi.org/10.1158/1538-7445.AM2024-4663
  45. Wu T. Research on bioinformatics: Characterizing EGFR-TKIs. Insights in Science, Engineering and Technology. 2023 Dec 22;5(4):175-184. https://doi.org/10.34207/ibseet.2023.54021
  46. Zhang X, Liu E, Song Y, Yu P, Rediar S, Yu L. Abstract 6509. Dependence of EGFR-mutant NSCLC on MET as demonstrated by vebreltinib, a novel and selective brain-penetrating MET kinase inhibitor. Cancer Research. 2024 Mar 22;84(6_Supplement):6509. https://doi.org/10.1158/1538-7445.AM2024-6509
  47. Yang Y, He X, Xiao W, Bai J, Li Y. Ensartinib is effective in the treatment of advanced non-small cell lung cancer with MET amplification after multiple ALK-TKIs resistance: a case report. Anti-Cancer Drugs. 2024 Mar 1;35(2):252-4. https://doi.org/10.1097/CAD.0000000000001394
  48. Scanlon E, Lavery A, Abhrabri M, Stevenson L, Kennedy C, Byrne R, Walker A, Mullan-Young B, McMullan D, Curtis S, Heuson C, Turville I, Collinson D, Midgley R, Davidson N, Schrijver WAME, McGloin S, James TA, Craig SG, Blayney JK, Petty R, Hanlon R, Kennedy RD, Fallow MJW, Middleton M, Hanna G, Tunjiakin A. Neoadjuvantosimertinib with/without chemotherapy for EGFR-mutant lung adenocarcinoma: a translational study of the neoadjuvant cohort. Journal of Thoracic Oncology. 2024 Nov 14:S1556-0864(24)01930. https://doi.org/10.1016/j.jtho.2024.10.006
  49. Johnson ML, Girda E, Sohal D, Lakhani NJ, Olszanski AJ, Fong L, Kinnaman M, Han H, Moesta A, Hao Y, Li S, Jänne PA. Phase 1/2 study of REGN7075 (EGFR×CD28) combined with cemiplimab in patients with advanced solid tumors. Journal of Clinical Oncology. 2024 May 20;42(16_suppl):TPS2674. https://doi.org/10.1200/JCO.2024.42.16_suppl.TPS2674
  50. Lin JJ, Gainor JF. Current opportunities and challenges in ALK-positive lung cancer. Translational Lung Cancer Research. 2024 Jan 22;13(1):1. https://doi.org/10.21037/tlcr-2023-4
  51. Bhargava P, Robinson MO. Development of second-generation VEGFR tyrosine kinase inhibitors: current status. Current Oncology Reports. 2011 Apr;13(2):103-44. https://doi.org/10.1007/s11912-011-0142-4
  52. Xu L, Xu B, Wang J, Song Y, He X, Xia Y, Ye X. Recent advances of novel fourth generation EGFR inhibitors in overcoming C797S mutation of lung cancer therapy. European Journal of Medicinal Chemistry. 2021 May;217:113372. https://doi.org/10.1016/j.ejmech.2021.113372
  53. Mesquita L, Vargas A, Planchard D. Safety of osimertinib in EGFR-mutated non-small cell lung cancer. Expert Opinion on Drug Safety. 2018 Dec 2;17(12):1239-48. https://doi.org/10.1080/14740338.2018.1534289
  54. Li Y, Mo S, Wang J, Zheng H, Xu R, Cao P, Yang S, Zhu L, Guo S, Zhao K, Tian Y, Shen H, Lin F. Toward the next generation EGFR inhibitors: an overview of osimertinib resistance mediated by EGFR mutations in non-small cell lung cancer. Cell Communication and Signaling. 2023 Dec;21:136. https://doi.org/10.1186/s12964-023-01138-3
  55. Rivas S, Marín A, Samtani S, González-Feliú E, Armisén R. MET signaling pathways, resistance mechanisms, and therapeutic opportunities. Int J Mol Sci. 2022;23(22):13898. https://doi.org/10.3390/ijms232213898
  56. Yonesaka K. HER2-/HER3-targeting antibody-drug conjugates for treating lung and colorectal cancers resistant to EGFR inhibitors. Cancers. 2021;13(5):1047. https://doi.org/10.3390/cancers13051047
  57. Huang L, Guo Z, Wang F, Fu L. KRAS mutation: from undruggable to druggable in cancer. Signal Transduction and Targeted Therapy. 2021 Nov 15;6(1):386. https://doi.org/10.1038/s41392-021-00788-4
  58. Poulikakos PI, Sullivan RJ, Yaeger R. Molecular pathways and mechanisms of BRAF in cancer therapy. Clinical Cancer Research. 2022 Nov 15;28(21):4559–72. https://doi.org/10.1158/1078-0432.CCR-21-1148
  59. Sienc C, Compes A, Nill M, Borchmann S, Odenthal M, Florin A, Brägelmann J, Büttner R, Meder L, Ullrich RT. EGFR inhibition strongly modulates the tumour immune microenvironment in EGFR-driven non-small-cell lung cancer. 2022 Aug 15;64(14):1983–99. https://doi.org/10.3390/cancers14181983
  60. Garg M. Emerging roles of epithelial–mesenchymal plasticity in invasion–metastasis cascade and therapy resistance. Cancer and Metastasis Reviews. 2022 Mar;41(1):43–68. https://doi.org/10.1007/s10555-021-09983-8
  61. Lim SM, Cho BC, Han Y, Kim SW, Lee KH, Nagasaka M, Jo A, Seoh K, Kim C, Reungwetwattana T. Phase 1/1b clinical trial of YH25448, a 3rd generation EGFR-TKI, in patients with 3rd generation EGFR-TKI resistance in EGFR mutated advanced/metastatic non-small cell lung cancer (NSCLC). Journal of Clinical Oncology. 2024;42(16_suppl):TPS8568. https://doi.org/10.1200/JCO.2024.42.16_suppl.TPS8568
  62. Dickerson D, Diogo A, Al M. Epidermal growth factor receptor (EGFR) in various cancer types: existing inhibitors in the clinic and future approaches.International Journal of Molecular Sciences. 2024 Sep 17;25(18):10008. https://doi.org/10.3390/ijms251810008
  63. Dou D, Zhang X, Wang J, Wumaier G, Qiao Y, Xie L, Jiang W, Sha W, Li W, Mei W, Zhang C, He H, Wang C, Wu L, Diao Y, Zhu L, Zhao Z, Chen Z, Xu Y, Li S, Li H. Design, synthesis, and biological evaluation of diphenyl ether substituted quinazolin-4-amine derivatives as potent EGFRL858R/T790M/C797S inhibitors. European Journal of Medicinal Chemistry. 2024 Dec 5;279:116858. https://doi.org/10.1016/j.ejmech.2024.116858
  64. Corvaja C, Passaro A, Attili I, Aldrighetti G, Spitaleri G, Del Signore ÊED, de Marinis F. Advancements in fourth-generation EGFR TKIs in EGFR-mutant NSCLC: distinguishing biological insights and therapeutic development. Cancer Treatment Reviews. 2024 Sep;124:103824. https://doi.org/10.1016/j.ctrv.2024.103824
  65. Thomson C, Braybrooke E, Colclough N, Davies NJ, Floch N, Greenwood R, Guérot C, Hargreaves D, Johnstone P, Khurana S, Kotomori HJ. Optimization of Potent, Efficacious, Selective and Blood–Brain Barrier Penetrating Inhibitors Targeting EGFR Exon20 Insertion Mutations. Journal of Medicinal Chemistry. 2024 Oct 3. https://doi.org/10.1021/acs.jmedchem.4c01547
  66. Dudgeon C, Fujiyama S, Funk O, Tamirefa F, Kangas TO, Zhang W, Lightcap ES, Surguladze D, Bose N. LHSparc-4665/FCN-7366, a potent GCN2 kinase activator, augments osimertinib therapy to delay resistance in EGFR mutant NSCLC models. Cancer Research. 2024 Mar 22;84(Suppl_16_Supplement):4665. https://doi.org/10.1158/1538-7445.AM2024-4665
  67. Lee E, Oh SY, Lee WN, Kim JY, Kim MJ, Kim TH, Jeong MS, Lim SM, Baum A, Weingberger L, Engelhart H, Petronczki M, So M, Yun M, Cho BC. Discovery of a novel potent EGFR inhibitor against EGFR activating mutations and on-target resistance in NSCLC. Clinical Cancer Research. 2024 Apr 19:clincanres.0567.2023. https://doi.org/10.1158/1078-0432.CCR-23-2561
  68. Lin JJ, Gainor JF. Current opportunities and challenges in ALK-positive lung cancer. Translational Lung Cancer Research. 2024 Jan 1;13(1). https://doi.org/10.21037/tlcr-2023-021
  69. Go Y, Yoshieka S, Yoshida N, Yoshimi S, Kouzaiho A, Toya K, Kurumida K, Ogasaw T, Tsuchii T, Yamaguchi F. Prolonged survival in osimertinib-resistant EGFR-mutated adenocarcinoma. Current Problems in Cancer. 2024 Oct 18:105392. https://doi.org/10.1016/j.currproblcancer.2024.105392
  70. Rocco D, Della Gravara L, Boccia MC, Palaoro G, Gridelli C. Novel combination of anti-angiogenesis in adenocarcinoma NSCLC with EGFR activating mutations. 2024 Sep 7;28(3):237–46. https://doi.org/10.3390/targets20300164
  71. Kermost H. Combination of ramucirumab and osimertinib for EGFR-mutated non-small cell lung cancer: Phelps for new beginnings. Journal of Clinical Oncology. 2024 Oct 15;20–24. https://doi.org/10.1200/JCO.24.01592
  72. Liu LJ, Li H, Chen CY, Li TT, Deng B, Ling Z, Liu J. Efficacy evaluation of targeted therapy in EGFR-mutated advanced lung adenocarcinoma. Current Problems in Cancer. 2024 Aug;48(4):100873. https://doi.org/10.1016/j.currproblcancer.2024.100873
  73. Nguyen JP, Woerner LC, Johnson DE, Grandis JR. Future investigation directions for novel therapeutic targets in head and neck cancer. Expert Review of Anticancer Therapy. 2024 Feb 1;24(2):123–40. https://doi.org/10.1080/14737140.2024.2470872
  74. Papavasileiou KA, Sofianid A, Dgoua VA, Papavasileiou AS. The emerging role of angiogenesis in shaping the lung cancer microenvironment. 2024 Oct 18;13(20):1793. https://doi.org/10.3390/cells13201793
  75. Guo J, Liu F, Liu X, Fu B, Bais Q, Ren W, Kong D, Xu B, Sun X, Zhang Y, Cai W, Wang D, Chen C, Ren S, Zhou C, Lin J, Ding W, Wang J. BLU-945, a highly potent, CNS-penetrant 4th generation EGFR inhibitor overcoming major EGFR resistance mutations in NSCLC. Cancer Research. 2024 Mar 22;84(Suppl_16_Supplement):5514. https://doi.org/10.1158/1538-7445.AM2024-5514
  76. Ansari MJ, Bokov D, Markov A, Jalil AT, Shalaby MN, Suksatan W, Chupradit S, Al-Ghamdi HS, Shomali N, Zamani A, Mohammadi A. Cancer combination therapies by angiogenesis inhibitors; a comprehensive review. Cell Communication and Signaling. 2022 Apr 7;20(1):49.
  77. Aggarwal V, Kim C. J.39 MET point mutations as the mechanism of resistance to EGFR-TKI therapy: A case report of MET H1094Y-mediated resistance to osimertinib overcoming by capmatinib and a systematic review. Journal of Thoracic Oncology. 2024 Oct 1;19(10):S637. https://doi.org/10.1016/j.jtho.2024.09.1148 https://doi.org/10.1186/s12964-022-00838-y
  78. Kageji H, Momose T, Ebisawa M, Nakazawa Y, Okada H, Togashi N, Nagamoto Y, Obuchi W, Yasumatsu I, Kihara K, Hiramoto K, Minami M, Kasamuki N, Isoyama T, Naito H, Tanaka N. Discovery of a potent, selective, and orally active EGFR C797S mutant inhibitor (D05866293) with in vivo antitumor activity. Bioorganic & Medicinal Chemistry. 2024 Sep 1;141:117862. https://doi.org/10.1016/j.bmc.2024.117862
  79. Cheng WC, Lin CC, Liao WC, Lin CY, Chen CH, Chen IU, Tu CY, Hsia TC. The difference between combination and bifatinib in effectiveness and safety in first-line treatment of patients with advanced EGFR-mutant non-small cell lung cancer: a real-world observational study. BMC Cancer. 2022 Feb 19;24(1):228. https://doi.org/10.1186/s12885-024-11956-w
  80. Chmielecki J, Gray JE, Cheng Y, Ohe Y, Imamura F, Cho BC, Lin MC, Majem M, Shah R, Rukazenkov Y, Todd A, Markovets A, Barrett JC, Hatamie R, Banalemnis S. osimertinib plus savolitinib versus osimertinib monotherapy in EGFR-mutated advanced non-small cell lung cancer. Nature Communications. 2023 Feb 27;14(1):1070. https://doi.org/10.1038/s41467-023-36917-8
  81. Tian X, Gu T, Lee MH, Dong Z. Challenge and countermeasures for EGFR targeted therapy in non-small cell lung cancer. Reviews on Cancer (BiochimicaetBiophysicaActa). 2022 Jan 1;1877(1):188645. https://doi.org/10.1016/j.bbcan.2021.188645
  82. Waks AG, Martínez-Sáez O, Tarantino P, Braso-Maristany F, Pascual T, Cortés J, Tolaney SM, Prat A. Dual HER2 inhibition: mechanisms of synergy, patient selection, and resistance. Nature Reviews Clinical Oncology. 2024 Sep 13;21(11):***8118. https://doi.org/10.1038/s41571-024-00932-9
  83. Tapia M, Hernando C, Martínez MT, Burgue s, Tober-Sánchez C, Lameirinhas A, Ágreda-Roca A, Torres-Ruiz S, Garrido-Cano I, Luch A, Bermejo E, Eroles P. Clinical impact of new treatment strategies for HER2-positive metastatic breast cancer patients with resistance to classical anti-HER therapies. 2023 Sep 12;15(18):4522. https://doi.org/10.3390/cancers15184522
  84. Passaro A, Al Banji M, Hamilton EG, Dihen M, André F, Roy-Chowdhuri S, Mountzios G, Wistuba II, Swanton C, Peters S. Cancer biomarkers: emerging concepts and clinical implications for personalised treatment. 2024 Mar 28;187(7):1617-28. https://doi.org/10.1016/j.cell.2024.02.041
  85. Wang M, Herbst RS, Boshoff C. Toward personalized treatment approaches for non-small-cell lung cancer. Nature Medicine. 2021 Aug;27(8):1345-56. https://doi.org/10.1038/s41591-021-01450-2
  86. Wensink GE, Elias SG, Mullenders J, Koopman M, Bosj E, Kranenburg OW, Doornebal CW. Patient-derived organoids as a predictive biomarker for treatment response in cancer patients. npj Precision Oncology. 2021 Apr 12;5(1):30. https://doi.org/10.1038/s41698-021-00185-y
  87. Marrocco I, Yarden Y. Resistance of lung cancer to EGFR-specific kinase inhibitors: activation of bypass pathways and endogenous mutators. Cancers (Basel). 2023;15(20):5009. https://doi.org/10.3390/cancers15205009
  88. Sanborn RE, Schnieders FL, Senan S, Gadgeel SM. Beyond checkpoint inhibitors: enhancing antitumor immune response in lung cancer. American Society of Clinical Oncology Educational Book.American Society of Clinical Oncology Annual Meeting. 2022 Jun 7;42:e833-45. https://doi.org/10.1200/EDBK_350967
  89. Corke L, Sacher A. New strategies and combinations to improve outcomes in Immunotherapy in metastatic non-small-cell lung cancer. Current Oncology. 2021 Dec 23;29(1):38-55. https://doi.org/10.3390/curroncol29010004
  90. Laface C, Maselli FM, Santoro AN, Isia ML, Ambrogio F, Laterza M, Guarini C, De Santis P, Perrone M, Fedele P. The resistance to EGFR-TKIs in non-small cell lung cancer: from molecular mechanisms to clinical application of new therapeutic strategies. 2023 May 27;15(6):1604. https://doi.org/10.3390/ph15061604
  91. Reita D, Pabst L, Pencreach E, Guérin E, Dano L, Rimelen V, Voegeli AC, Vallet J, Mascaux C, Beau-Faller M. Molecular mechanism of EGFR-TKI resistance in EGFR-mutated non-small cell lung cancer: application to biological diagnostic and monitoring. 2021 Sep 30;13(19):4926. https://doi.org/10.3390/cancers13194926
  92. Kobayashi K, Tan AC. Unraveling the impact of intratumoral heterogeneity on EGFR tyrosine kinase inhibitor resistance in EGFR-mutated NSCLC. International Journal of Molecular Sciences. 2023 Feb 18;24(4):4126. https://doi.org/10.3390/ijms24044126
  93. Labrie M, Brugge JS, Mills GB, Zervantonakis IK. Therapy resistance: opportunities created by adaptive responses to targeted therapies in cancer. Nature Reviews Cancer. 2022 Jun;22(6):323-48. https://doi.org/10.1038/s41568-022-00454-5