Comprehensive Advances in Non-Small Cell Lung Cancer: From Molecular Mechanisms to Precision Therapy

Authors

  • Jiayi Sun

DOI:

https://doi.org/10.61173/7f0ccx82

Keywords:

-Non-small cell lung cancer (NSCLC), Drug resistance, Antibody-drug conjugates, Precision medicine

Abstract

Accounting for the highest cancer-related death burden worldwide, NSCLC, presents a significant public health challenge due to its high incidence and persistently low survival rates. Despite progress in low-dose spiral CT screening and smoking cessation campaigns, the five-year survival rate for patients diagnosed at advanced stages remains below 20%, underscoring the urgent need for optimized treatment strategies. This article synthesizes recent research advances concerning pathogenic mechanisms, diagnostic classification, and therapeutic innovations. It begins by dissecting the interaction networks between driver gene mutations and the tumor immune microenvironment, elucidating the critical role of epigenetic dysregulation in tumor progression. It subsequently reviews how the integration of liquid biopsy with artificial intelligence (AI)-enhanced imaging techniques is refining molecular subtyping. The article then provides a systematic evaluation of breakthrough clinical developments, including the iterative evolution of targeted agents (such as fourth-generation EGFR inhibitors), the expansion of immunotherapy across all treatment lines (from neoadjuvant settings to advanced disease), and the emergence of antibody-drug conjugates (ADCs) targeting HER3 and TROP2. These transformative approaches have propelled the median survival of advanced patients beyond 30 months and increased the pathological complete response rate in early-stage patients by tenfold. Studies demonstrate that biomarker-directed precision therapy is profoundly reshaping clinical practice. Future efforts must prioritize unraveling complex resistance mechanisms to further extend therapeutic benefits to all patient populations through multi-omics-guided personalized combination strategies.

References

[1] H. Sung, J. Ferlay, R. L. Siegel, et al., “Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries,” CA Cancer J. Clin., vol. 71, no. 3, pp. 209–249, 2021.

[2] W. D. Travis, E. Brambilla, A. G. Nicholson, et al., “The 2015 World Health Organization Classification of Lung Tumors,” J. Thorac. Oncol., vol. 10, no. 9, pp. 1243–1260, 2015.

[3] N. Howlader, G. Forjaz, M. J. Mooradian, et al., “The Effect of Advances in Lung-Cancer Treatment on Population Mortality,” N. Engl. J. Med., vol. 383, no. 7, pp. 640–649, 2020.

[4] T. J. Lynch, D. W. Bell, R. Sordella, et al., “Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to Gefitinib,” N. Engl. J. Med., vol. 350, no. 21, pp. 2129–2139, 2004.

[5] F. Skoulidis, B. T. Li, G. K. Dy, et al., “Sotorasib for Lung Cancers with KRAS p.G12C Mutation,” N. Engl. J. Med., vol. 384, no. 25, pp. 2371–2381, 2021.

[6] A. T. Shaw, D. W. Kim, K. Nakagawa, et al., “Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer,” N. Engl. J. Med., vol. 368, no. 25, pp. 2385–2394, 2013.

[7] A. Brand, K. Singer, G. E. Koehl, et al., “LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells,” Cell Metab., vol. 24, no. 5, pp. 657–671, 2016.

[8] A. A. Chaudhuri, J. J. Chabon, A. F. Lovejoy, et al., “Early Detection of Molecular Residual Disease in Localized Lung Dean&Francis ISSN 2959-409X Cancer by Circulating Tumor DNA Profiling,” Cancer Discov., vol. 7, no. 12, pp. 1394–1403, 2017.

[9] A. Hosny, C. Parmar, J. Quackenbush, et al., “Artificial Intelligence in Radiology,” Nat. Rev. Cancer, vol. 18, no. 8, pp. 500–510, 2018.

[10] M. D. Hellmann, T. E. Ciuleanu, A. Pluzanski, et al., “Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden,” N. Engl. J. Med., vol. 378, no. 22, pp. 2093–2104, 2018.

[11] J. C. Soria, Y. Ohe, J. Vansteenkiste, et al., “Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer,” N. Engl. J. Med., vol. 378, no. 2, pp. 113–125, 2018.

[12] P. A. Jänne, G. J. Riely, S. M. Gadgeel, et al., “Adagrasib in Non–Small-Cell Lung Cancer Harboring a KRASG12C Mutation,” N. Engl. J. Med., vol. 387, no. 2, pp. 120–131, 2022.

[13] P. M. Forde, J. Spicer, S. Lu, et al., “Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer,” N. Engl. J. Med., vol. 386, no. 21, pp. 1973–1985, 2022.

[14] H. A. Yu, Y. Goto, H. Hayashi, et al., “HERTHENA-Lung01: Patritumab Deruxtecan in EGFR-Mutated NSCLC,” J. Clin. Oncol., vol. 41, no. 36_suppl, LBA9015, 2023.

[15] C. Zhou, S. S. Ramalingam, T. M. Kim, et al., “Treatment Outcomes and Safety of Mobocertinib in EGFR Exon 20 Insertion–Positive Metastatic Non–Small Cell Lung Cancer,” JAMA Oncol., vol. 9, no. 9, pp. 1260–1268, 2023.

[16] L. Paz-Ares, T. E. Ciuleanu, M. Cobo, et al., “Firstline Nivolumab plus Ipilimumab with Chemotherapy versus Chemotherapy Alone for Metastatic NSCLC,” Lancet Oncol., vol. 24, no. 12, pp. 1309–1322, 2023.

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Published

2025-08-26