Kannan Koteeswaran, Mohan Sumithra
Department of Pharmacology, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, Tamil Nadu, 603 203, India.
Med Oncol. 2025 May 5;42(6):196. doi: 10.1007/s12032-025-02755-9.
Lung cancer remains the second leading cause of cancer-related morbidity and mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have become the standard first-line therapy for advanced NSCLC with EGFR mutations, offering significant improvements in progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) compared to chemotherapy alone. Recent studies suggest that their effectiveness decreased with the emergence of acquired resistance, such as C797S and T790M. Immunotherapy alone also shows enhanced PFS and OS over chemotherapy; however, its applicability can be limited in cases with low programmed cell death ligand 1 (PD-L1) expression and result in immune-related adverse effects like those observed in retrospective, non-randomized studies. Emerging fourth-generation EGFR-TKIs, currently under clinical trials, show promising potential to address these resistance mechanisms. Advanced inhibitors, including BBT-176, BLU-945, and BLU-701, have effectively targeted resistant mutations and reduced disease progression. Studies have suggested that combining fourth-generation EGFR-TKIs with immunotherapies targeting novel pathways like LAG-3 and TIM-3 may enhance patient outcomes. Such combination regimens aim to optimize PFS, OS, and ORR while minimizing adverse effects and addressing the limitations of current therapies. This study explores the landscape of EGFR mutations, their clinical significance, and the integration of innovative fourth-generation EGFR-TKIs with immunotherapies, emphasizing the potential of precision medicine in advancing the management of EGFR-mutated NSCLC.
肺癌仍然是全球癌症相关发病和死亡的第二大主要原因，其中非小细胞肺癌（NSCLC）占大多数病例。表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）已成为晚期EGFR突变NSCLC的标准一线治疗方法，与单纯化疗相比，在无进展生存期（PFS）、总生存期（OS）和客观缓解率（ORR）方面有显著改善。最近的研究表明，随着获得性耐药（如C797S和T790M）的出现，其有效性会降低。单独使用免疫疗法在PFS和OS方面也优于化疗；然而，在程序性细胞死亡配体1（PD-L1）表达低的情况下，其适用性可能有限，并会导致免疫相关不良反应，如回顾性、非随机研究中观察到的那些反应。目前正在进行临床试验的新兴第四代EGFR-TKIs显示出解决这些耐药机制的潜在前景。包括BBT-176、BLU-945和BLU-701在内的先进抑制剂已有效靶向耐药突变并减少疾病进展。研究表明，将第四代EGFR-TKIs与针对LAG-3和TIM-3等新途径的免疫疗法联合使用可能会改善患者预后。这种联合治疗方案旨在优化PFS、OS和ORR，同时将不良反应降至最低，并解决当前疗法的局限性。本研究探讨了EGFR突变的情况、其临床意义以及创新的第四代EGFR-TKIs与免疫疗法的整合，强调了精准医学在推进EGFR突变NSCLC治疗中的潜力。
