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  • Review Article
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Navigating the landscape of EGFR TKI resistance in EGFR-mutant NSCLC — mechanisms and evolving treatment approaches

Nature Reviews Clinical Oncology volume 23, pages 63–83 (2026) Cite this article

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Abstract

Resistance to EGFR tyrosine kinase inhibitors (TKIs) remains a major obstacle in the clinical management of EGFR-mutant non-small-cell lung cancer (NSCLC). Despite the transformative therapeutic activity of the multiple iterations of EGFR TKIs, spanning from first-generation reversible inhibitors such as erlotinib and gefitinib to the current standard-of-care third-generation covalent inhibitor osimertinib, primary or acquired resistance to these agents inevitably emerges via diverse mechanisms. The advent of combination therapies that incorporate chemotherapy, anti-angiogenic agents, bispecific antibodies or antibody–drug conjugates has increased clinical benefit but introduced new resistance phenotypes, underscoring the dynamic plasticity and complexity of tumour evolution under therapeutic pressure. In this Review, we provide a comprehensive synthesis of the molecular mechanisms that underlie resistance to third-generation EGFR TKIs, describe biomarker-guided and biomarker-unselected therapeutic strategies to overcome these mechanisms, and discuss emerging approaches to pre-empt resistance through early application of combination therapies. We highlight the paradigm shift from radiological to molecular monitoring of resistance to therapy and explore how advances in circulating tumour DNA analysis, artificial intelligence and multi-omics might facilitate adaptive treatment strategies. As the therapeutic landscape evolves, a more complete mechanistic understanding of resistance will be essential to guide rational treatment sequencing, inform trial design and improve long-term outcomes for patients with EGFR-mutant NSCLC.

Key points

  • EGFR tyrosine kinase inhibitors (TKIs) have revolutionized the management of EGFR-mutant non-small-cell lung cancer (NSCLC); however, resistance to these agents is inevitable in most patients.

  • Resistance to EGFR TKIs is categorized as primary or secondary and can be driven by on-target mutations, bypass signalling or lineage transformation.

  • A paradigm shift from radiological to molecular monitoring of resistance via circulating tumour DNA (ctDNA) assessment has enabled the earlier detection and monitoring of drug resistance, potentially providing better insights into the underlying mechanisms.

  • Strategies to overcome resistance include biomarker-guided approaches, for example, using fourth-generation EGFR TKIs, EGFR–MET bispecific agents and certain antibody–drug conjugates (ADCs) such as those that target HER2 or MET, as well as biomarker-unselected treatments such as TROP2-targeted or HER3-targeted ADCs and immune-checkpoint inhibitor-based combinations.

  • Efforts to delay resistance focus on eliminating drug-tolerant persister cells using EGFR TKIs plus chemotherapy and/or radiotherapy, as well as pre-emptively blocking resistance pathways with EGFR and MET dual-targeted combinations, to prolong clinical benefit.

  • Future directions emphasize adaptive therapy guided by ctDNA dynamics, multi-omic profiling of resistance pathways and artificial intelligence-based prediction models to individualize treatment sequencing and optimize long-term outcomes in patients with EGFR-mutant NSCLC.

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Fig. 1: Mechanisms of secondary resistance to third-generation EGFR TKIs and corresponding management strategies.
The alternative text for this image may have been generated using AI.
Fig. 2: Management strategies for EGFR TKI resistance in advanced-stage EGFR-mutant NSCLC.
The alternative text for this image may have been generated using AI.

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Acknowledgements

The work of the authors is supported by the National Natural Science Foundation of China (grant 82422001).

Author information

Author notes

  1. These authors contributed equally: Jing Zhao, Wanting Xu, Fei Zhou.

Authors and Affiliations

  1. Department of Medical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China

    Jing Zhao

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

    Wanting Xu, Xiangyu Zhang, Mo Zhou, Da Miao, Lan Yu, Wen Li & Yang Xia

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

    Fei Zhou & Caicun Zhou

  4. Clinical Trials Center, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China

    Yongchang Zhang

  5. Department of Thoracic Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China

    Junqiang Fan

  6. Cancer Center, Zhejiang University, Hangzhou, China

    Wen Li & Yang Xia

  7. State Key Laboratory of Translational Oncology, Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China

    Tony Mok & Molly Li

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

    Xiuning Le

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  1. Jing Zhao
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All authors made substantial contributions to all aspects of the preparation of this manuscript.

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Correspondence to Xiuning Le, Molly Li or Yang Xia.

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T.M. has received research funding (to institution) from AstraZeneca, Bristol Myers Squibb (BMS), G1 Therapeutics, MSD, Merck Serono, Novartis, Pfizer, Roche, SFJ Pharmaceuticals, Takeda and XCovery; consulting fees from and/or been an advisory board member for AbbVie, ACEA Therapeutics, Adagene, Alentis Therapeutics, Alpha Biopharma, Amgen, Amoy Diagnostics, AnHeart Therapeutics, AstraZeneca, AVEO Pharmaceuticals, Bayer, BeiGene, BerGenBio, Berry Oncology, Blueprint Medicines, Boehringer Ingelheim, BMS, Bowtie Life Insurance, Bridge Biotherapeutics, C4 Therapeutics, Cirina, Covidien, CStone Pharmaceuticals, Curio Science, D3 Bio, Da Volterra, Daiichi Sankyo, Eisai, Elevation Oncology, F. Hoffmann-La Roche, Fishawack Facilitate, G1 Therapeutics, geneDecode, Genentech, Gilead, GLG, Gritstone Oncology, Guardant Health, Hengrui Therapeutics, HutchMed, Ignyta, Illumina, Imagene AI, Incyte, Inivata, InxMed, IQVIA, Janssen, Johnson & Johnson, Lakeshore Biotech, Lilly, Loxo Oncology, Lucence Health, Lunit USA, Medscape, Medtronic, Merck Serono, Mirati Therapeutics, MiRXES, MoreHealth, MSD, New Frontier, Ningbo Newbay Technology Development, Novartis, Novocure, Omega Therapeutics, OrigiMed, OSE Immunotherapeutics, Phanes Therapeutics, PeerVoice, Pfizer, Prenetics, PrIME Oncology, Puma Biotechnology, Qiming Development, Regeneron, Roche/Foundation Medicine, Sanofi–Aventis, Schrödinger, SFJ Pharmaceuticals, Simcere of America, Simcere Zaiming, Summit Therapeutics, Synergy Research, Takeda, Tigermed, Vertex, Virtus Medical, XENCOR and Yuhan Corporation; speaker’s fees from ACEA Therapeutics, Alpha Biopharma, Amgen, Amoy Diagnostics, AstraZeneca, BeiGene, Boehringer Ingelheim, BMS, Daiichi Sankyo, Daz Group, Fishawack Facilitate, InMed Medical Communication, Janssen, Jiahui Holdings, LiangYiHui Healthcare, Lilly, Lucence Health, MD Health Brazil, Medscape, Merck, MiRXES, MSD, Novartis, OrigiMed, PeerVoice, P. Permanyer, Pfizer, Physicians’ Education Resource, PrIME Oncology, Research to Practice, Roche/Foundation Medicine, Sanofi–Aventis, Shanghai BeBirds, Shanghai Promedican Pharmaceuticals, Taiho, Takeda and Touch Independent Medical Education; has stock or other ownership interests in ACT Genomics–Sanomics Group Oncology, Alentis Therapeutics, AstraZeneca, Aurora Tele-Oncology, Biolidics, Bowtie Life Insurance, D3 Bio, HutchMed, Illumos, Insighta, Lakeshore Biotech, Lunit USA, Phanes Therapeutics, Prenetics and Virtus Medical; and serves as a board member and/or has leadership roles at AstraZeneca, Aurora Tele-Oncology, Altum, EPOCH Biosciences, Genómica, HutchMed and Insighta, all outside the submitted work. X.L. has received consulting or advisory fees from AbbVie, Abion Bio, ArriVent, AstraZeneca, Bayer, BlossomHill Therapeutics, Blueprint Medicines, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, EMD Serono (Merck), Hengrui Therapeutics, Janssen, Novartis, Regeneron, Sensei Biotherapeutics, Spectrum Pharmaceuticals, SystImmune, Taiho and Teligene; research funding (to institution) from ArriVent, Boehringer Ingelheim, Dizal, Eli Lilly, EMD Serono, Janssen, Regeneron, Takeda, Teligene and ThermoFisher; and travel support from EMD Serono, Janssen and Spectrum Pharmaceutics. The other authors declare no competing interests.

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Nature Reviews Clinical Oncology thanks E. Smit, who co-reviewed with J. Nutzinger; M.-J. Ahn and F. Facchinetti for their contribution to the peer review of this work.

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Zhao, J., Xu, W., Zhou, F. et al. Navigating the landscape of EGFR TKI resistance in EGFR-mutant NSCLC — mechanisms and evolving treatment approaches. Nat Rev Clin Oncol 23, 63–83 (2026). https://doi.org/10.1038/s41571-025-01085-z

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