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第三代EGFR-TKIs耐药后药物治疗研究进展
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Abstract:
第三代表皮生长因子受体–酪氨酸激酶抑制剂(EGFR-TKIs)显著改善了局部晚期及转移性非小细胞肺癌(NSCLC)患者的无进展生存期(PFS)及总生存期(OS),但耐药问题限制了其长期疗效。在三代EGFR-TKs耐药后,根据耐药机制调整靶向药物治疗,包括换用一/二代靶向药物、联合赛沃替尼、特泊替尼等特定靶点药物可使部分NSCLC患者获益。现有研究表明,以化疗为基础的联合治疗,包括联合免疫治疗、靶向治疗及抗血管药物治疗可延长NSCLC患者的PFS,但其不良反应需引起重视。抗体药物偶联物(ADC)、第四代EGFR-TKIs及双特异性抗体等新型抗肿瘤药物在临床试验中显示出潜在疗效,为三代EGFR-TKIs治疗后进展的NSCLC患者提供了新的选择。未来研究应进一步探索其耐药机制,同时优化药物联合治疗策略,为NSCLC患者的后线治疗提供有效、安全的治疗方案。
The third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have significantly improved progression-free survival (PFS) and overall survival (OS) in patients with locally advanced and metastatic non-small cell lung cancer (NSCLC). However, the emergence of drug resistance limits their long-term efficacy. Following resistance to third-generation EGFR-TKIs, adjusting targeted therapy based on resistance mechanisms—such as switching to first- or second-generation targeted agents, or combining with specific targeted drugs like savolitinib or tepotinib—can benefit some NSCLC patients. Current research indicates that chemotherapy-based combination therapies, including immunotherapy, targeted therapy, and anti-angiogenic agents, can extend PFS in NSCLC patients, though their adverse effects warrant careful attention. Novel anti-tumor agents such as antibody-drug conjugates (ADC), fourth-generation EGFR-TKIs, and bispecific antibodies have demonstrated potential efficacy in clinical trials, offering new options for NSCLC patients who have progressed after third-generation EGFR-TKIs treatment. Future studies should further explore resistance mechanisms and optimize combination therapy strategies to provide effective and safe treatment options for NSCLC patients in later-line settings.
[1] | Cheng, Y., He, Y., Li, W., Zhang, H., Zhou, Q., Wang, B., et al. (2021) Osimertinib versus Comparator EGFR TKI as First-Line Treatment for EGFR-Mutated Advanced NSCLC: FLAURA China, a Randomized Study. Targeted Oncology, 16, 165-176. https://doi.org/10.1007/s11523-021-00794-6 |
[2] | Zhou, Q., Zhao, H., Lu, S., Cheng, Y., Liu, Y., Zhao, M., et al. (2024) Consensus on the Lung Cancer Management after Third-Generation EGFR-TKI Resistance. The Lancet Regional Health, 53, Article 101260. https://doi.org/10.1016/j.lanwpc.2024.101260 |
[3] | Cooper, A.J., Sequist, L.V. and Lin, J.J. (2022) Third-Generation EGFR and ALK Inhibitors: Mechanisms of Resistance and Management. Nature Reviews Clinical Oncology, 19, 499-514. https://doi.org/10.1038/s41571-022-00639-9 |
[4] | Zalaquett, Z., Catherine Rita Hachem, M., Kassis, Y., Hachem, S., Eid, R., Raphael Kourie, H., et al. (2023) Acquired Resistance Mechanisms to Osimertinib: The Constant Battle. Cancer Treatment Reviews, 116, Article 102557. https://doi.org/10.1016/j.ctrv.2023.102557 |
[5] | Wang, Y., Yang, N., Zhang, Y., Li, L, Han, R., Zhu, M., et al. (2020) Effective Treatment of Lung Adenocarcinoma Harboring EGFR-Activating Mutation, T790M, and cis-C797s Triple Mutations by Brigatinib and Cetuximab Combination Therapy. Journal of Thoracic Oncology, 15, 1369-1375. https://doi.org/10.1016/j.jtho.2020.04.014 |
[6] | Wang, Z., Yang, J., Huang, J., Ye, J., Zhang, X., Tu, H., et al. (2017) Lung Adenocarcinoma Harboring EGFR T790M and in Trans C797S Responds to Combination Therapy of First-and Third-Generation EGFR TKIs and Shifts Allelic Configuration at Resistance. Journal of Thoracic Oncology, 12, 1723-1727. https://doi.org/10.1016/j.jtho.2017.06.017 |
[7] | Ricordel, C., Friboulet, L., Facchinetti, F. and Soria, J.-C. (2018) Molecular Mechanisms of Acquired Resistance to Third-Generation EGFR-TKIs in EGFR T790m-Mutant Lung Cancer. Annals of Oncology, 29, i28-i37. https://doi.org/10.1093/annonc/mdx705 |
[8] | Chmielecki, J., Mok, T., Wu, Y., Han, J., Ahn, M., Ramalingam, S.S., et al. (2023) Analysis of Acquired Resistance Mechanisms to Osimertinib in Patients with EGFR-Mutated Advanced Non-Small Cell Lung Cancer from the AURA3 Trial. Nature Communications, 14, Article No. 1071. https://doi.org/10.1038/s41467-023-35962-x |
[9] | Ahn, M., De Marinis, F., Bonanno, L., Cho, B.C., Kim, T.-M., Cheng, S., et al. (2022) EP08.02-140 MET Biomarker-Based Preliminary Efficacy Analysis in SAVANNAH: Savolitinib + Osimertinib in EGFRm NSCLC Post-Osimertinib. Journal of Thoracic Oncology, 17, S469-S470. https://doi.org/10.1016/j.jtho.2022.07.823 |
[10] | Kim, T.M., Guarneri, V., Jye, V.P., Khaw, L.B., Yang, J.-J., Wislez, M., et al. (2023) OA21.05 Tepotinib + Osimertinib in EGFR-Mutant NSCLC with MET Amplification Following 1L Osimertinib: INSIGHT 2 Primary Analysis. Journal of Thoracic Oncology, 18, S94. https://doi.org/10.1016/j.jtho.2023.09.106 |
[11] | Weng, C., Liu, K., Jin, S., Su, J., Yao, Y., Zhou, C., et al. (2024) Triple-targeted Therapy of Dabrafenib, Trametinib, and Osimertinib for the Treatment of the Acquired BRAF V600E Mutation after Progression on EGFR-Tyrosine Kinase Inhibitors in Advanced EGFR-Mutated Non-Small Cell Lung Cancer Patients. Translational Lung Cancer Research, 13, 2538-2548. https://doi.org/10.21037/tlcr-24-358 |
[12] | Li, C., Shao, J., Li, P., Feng, J., Li, J. and Wang, C. (2023) Circulating Tumor DNA as Liquid Biopsy in Lung Cancer: Biological Characteristics and Clinical Integration. Cancer Letters, 577, Article 216365. https://doi.org/10.1016/j.canlet.2023.216365 |
[13] | 中华医学会肿瘤学分会. 中华医学会肺癌临床诊疗指南(2024版) [J]. 中华肿瘤杂志, 2024, 46(9): 805-843. |
[14] | Lu, S., Wu, L., Jian, H., Cheng, Y., Wang, Q., Fang, J., et al. (2023) 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. The Lancet Respiratory Medicine, 11, 624-636. https://doi.org/10.1016/s2213-2600(23)00135-2 |
[15] | Patil, T., Gao, D., Watson, A., Sakamoto, M., Nie, Y., Gibson, A., et al. (2025) The Efficacy of Continuing Osimertinib with Platinum Pemetrexed Chemotherapy Upon Progression in Patients with Metastatic Non-Small Cell Lung Cancer Harboring Sensitizing EGFR Mutations. Lung Cancer, 199, Article 108040. https://doi.org/10.1016/j.lungcan.2024.108040 |
[16] | Morimoto, K., Sawada, R., Yamada, T., Azuma, K., Ito, K., Goto, Y., et al. (2022) A Real-World Analysis of Immune Checkpoint Inhibitor-Based Therapy after Osimertinib Treatment in Patients with EGFR-Mutant NSCLC. JTO Clinical and Research Reports, 3, Article 100388. https://doi.org/10.1016/j.jtocrr.2022.100388 |
[17] | Long, Y., Xiong, Q., Song, Q., Li, Y., Li, X., Qin, B., et al. (2021) Immunotherapy Plus Chemotherapy Showed Superior Clinical Benefit to Chemotherapy Alone in Advanced NSCLC Patients after Progression on Osimertinib. Thoracic Cancer, 13, 394-403. https://doi.org/10.1111/1759-7714.14271 |
[18] | Fu, Z., Li, S., Han, S., Shi, C. and Zhang, Y. (2022) Antibody Drug Conjugate: The “Biological Missile” for Targeted Cancer Therapy. Signal Transduction and Targeted Therapy, 7, [page]. https://doi.org/10.1038/s41392-022-00947-7 |
[19] | Ahn, M., Tanaka, K., Paz-Ares, L., Cornelissen, R., Girard, N., Pons-Tostivint, E., et al. (2025) Datopotamab Deruxtecan versus Docetaxel for Previously Treated Advanced or Metastatic Non-Small Cell Lung Cancer: The Randomized, Open-Label Phase III Tropion-Lung01 Study. Journal of Clinical Oncology, 43, 260-272. https://doi.org/10.1200/jco-24-01544 |
[20] | Sands, J., Ahn, M.-J., Lisberg, A., Cho, B.C., Blumenschein Jr, G., Shum, E., et al. (2025) Datopotamab Deruxtecan in Advanced or Metastatic Non-Small Cell Lung Cancer with Actionable Genomic Alterations: Results from the Phase II TROPION-Lung05 Study. Journal of Clinical Oncology. https://doi.org/10.1200/JCO-24-01349 |
[21] | Yu, H.A., Goto, Y., Hayashi, H., Felip, E., Chih-Hsin Yang, J., Reck, M., et al. (2023) HERTHENA-Lung01, a Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer after Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Platinum-Based Chemotherapy. Journal of Clinical Oncology, 41, 5363-5375. https://doi.org/10.1200/jco.23.01476 |
[22] | McGrath, L., Zheng, Y., Christ, S., Sachs, C.C., Khelifa, S., Windmüller, C., et al. (2023) Abstract 5737: Evaluation of the Relationship between Target Expression and in vivo Anti-Tumor Efficacy of AZD9592, an EGFR/c-MET Targeted Bispecific Antibody Drug Conjugate. Cancer Research, 83, 5737-5737. https://doi.org/10.1158/1538-7445.am2023-5737 |
[23] | AstraZeneca (2022) A Phase I, Multicenter, Open-label, First-in-Human, Dose Escalation and Expansion Study of AZD9592 as Monotherapy and in Combination with Anti-Cancer Agents in Patients with Advanced Solid Tumors. https://clinicaltrials.gov/study/NCT05647122. |
[24] | Yu, H., Johnson, M., Henry, J.T., Spira, A., Han, J., Barve, M., et al. (2023) Abstract C022: Phase 1 Study of BDTX-1535, an Oral 4th Generation Inhibitor, in Patients with Non-Small Cell Lung Cancer and Glioblastoma: Preliminary Dose Escalation Results. Molecular Cancer Therapeutics, 22, C022. https://doi.org/10.1158/1535-7163.targ-23-c022 |
[25] | Corvaja, C., Passaro, A., Attili, I., Aliaga, P.T., Spitaleri, G., Signore, E.D., et al. (2024) Advancements in Fourth-Generation EGFR TKIs in EGFR-Mutant NSCLC: Bridging Biological Insights and Therapeutic Development. Cancer Treatment Reviews, 130, Article 102824. https://doi.org/10.1016/j.ctrv.2024.102824 |
[26] | Passaro, A., Wang, J., Wang, Y., Lee, S.-H., Melosky, B., Shih, J.-Y., et al. (2024) Amivantamab Plus Chemotherapy with and without Lazertinib in EGFR-Mutant Advanced NSCLC after Disease Progression on Osimertinib: Primary Results from the Phase III MARIPOSA-2 Study. Annals of Oncology, 35, 77-90. https://doi.org/10.1016/j.annonc.2023.10.117 |
[27] | Fang, W., Zhao, Y., Luo, Y., Yang, R., Huang, Y., He, Z., et al. (2024) Ivonescimab Plus Chemotherapy in Non-Small Cell Lung Cancer with EGFR Variant: A Randomized Clinical Trial. JAMA, 332, 561-570. https://doi.org/10.1001/jama.2024.10613 |