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  • Review Article
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The changing treatment landscape of EGFR-mutant non-small-cell lung cancer

Nature Reviews Clinical Oncology volume 22, pages 95–116 (2025)Cite this article

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Abstract

The discovery of the association between EGFR mutations and the efficacy of EGFR tyrosine-kinase inhibitors (TKIs) has revolutionized the treatment paradigm for patients with non-small-cell lung cancer (NSCLC). Currently, third-generation EGFR TKIs, which are often characterized by potent central nervous system penetrance, are the standard-of-care first-line treatment for advanced-stage EGFR-mutant NSCLC. Rational combinations of third-generation EGFR TKIs with anti-angiogenic drugs, chemotherapy, the EGFR–MET bispecific antibody amivantamab or local tumour ablation are being investigated as strategies to delay drug resistance and increase clinical benefit. Furthermore, EGFR TKIs are being evaluated in patients with early stage or locally advanced EGFR-mutant NSCLC, with the ambitious aim of achieving cancer cure. Despite the inevitable challenge of acquired resistance, emerging treatments such as new TKIs, antibody–drug conjugates, new immunotherapeutic approaches and targeted protein degraders have shown considerable promise in patients with progression of EGFR-mutant NSCLC on or after treatment with EGFR TKIs. In this Review, we describe the current first-line treatment options for EGFR-mutant NSCLC, provide an overview of the mechanisms of acquired resistance to third-generation EGFR TKIs and explore novel promising treatment strategies. We also highlight potential avenues for future research that are aimed at improving the survival outcomes of patients with this disease.

Key points

  • Third-generation EGFR tyrosine-kinase inhibitors (TKIs) have become the standard-of-care first-line treatment for advanced-stage EGFR-mutant non-small-cell lung cancer (NSCLC). However, their efficacy appears to have plateaued, with the median progression-free survival duration not exceeding 2 years in pivotal trials for any approved third-generation EGFR TKI.

  • Rational combinations of third-generation EGFR TKIs with anti-angiogenic drugs, chemotherapy, the EGFR–MET bispecific antibody amivantamab or local tumour ablation are under investigation as strategies to delay resistance, prolong the duration of response and maximize treatment efficacy.

  • The therapeutic scope of EGFR TKIs has been expanded to include patients with resectable early stage and inoperable locally advanced NSCLC, marking a crucial milestone in the precision management of EGFR-mutant NSCLC.

  • At present, no biomarker-driven strategies have been approved for patients with NSCLC that is progressing on third-generation EGFR TKIs. By contrast, several chemotherapy-based, biomarker-agnostic approaches have been approved for clinical use, including chemotherapy plus amivantamab or ivonescimab, offering new avenues for addressing this critical unmet medical need.

  • Manipulating drug-resistant cells (including drug-tolerant persister cells, dormant cancer cells and cancer stem cells) could reduce the likelihood of resistance following effective EGFR TKI treatment. Although the mechanisms behind the persistence of these cells are not fully understood, local ablation of residual lesions (aimed at their elimination) has yielded promising results.

  • Circulating tumour DNA-guided analysis of molecular residual disease might provide valuable guidance for adaptive therapy in patients with EGFR-mutant NSCLC. Well-designed, prospective randomized clinical trials are needed.

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Fig. 1: Major advances in the use of EGFR tyrosine-kinase inhibitors to treat patients with non-small-cell lung cancer.
Fig. 2: Mechanisms of resistance to third-generation EGFR tyrosine-kinase inhibitors and potential treatment strategies.
Fig. 3: Potential strategies for the eradication of residual disease and persister cell populations.
Fig. 4: Integrating circulating tumour DNA into the management of EGFR-mutant non-small-cell lung cancer.

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Acknowledgements

F.Z. is supported in part by the National Natural Science Foundation of China (81703020) and the Natural Science Foundation of Shanghai (23ZR1453500). X.L. is supported by the Damon Runyon Foundation. S.S.R. is supported in part by the US National Cancer Institute and National Institutes of Health (P50CA217691). C.Z. is supported in part by the National Key R&D Program of China (2022YFC2505005) and the National Natural Science Foundation of China (82141101).

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  1. These authors contributed equally: Fei Zhou, Haoyue Guo, Yang Xia.

Authors and Affiliations

  1. Department of Medical Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China

    Fei Zhou, Haoyue Guo & Caicun Zhou

  2. Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China

    Yang Xia

  3. Department of Thoracic Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA

    Xiuning Le

  4. Division of Medical Oncology, National Cancer Centre Singapore, Duke-NUS Medical School, Singapore, Singapore

    Daniel S. W. Tan

  5. Department of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA, USA

    Suresh S. Ramalingam

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Zhou, F., Guo, H., Xia, Y. et al. The changing treatment landscape of EGFR-mutant non-small-cell lung cancer. Nat Rev Clin Oncol 22, 95–116 (2025). https://doi.org/10.1038/s41571-024-00971-2

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