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  • Review Article
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Third-generation EGFR and ALK inhibitors: mechanisms of resistance and management

Nature Reviews Clinical Oncology volume 19, pages 499–514 (2022)Cite this article

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An Author Correction to this article was published on 15 August 2022

This article has been updated

Abstract

The discoveries of EGFR mutations and ALK rearrangements as actionable oncogenic drivers in non-small-cell lung cancer (NSCLC) has propelled a biomarker-directed treatment paradigm for patients with advanced-stage disease. Numerous EGFR and ALK tyrosine kinase inhibitors (TKIs) with demonstrated efficacy in patients with EGFR-mutant and ALK-rearranged NSCLCs have been developed, culminating in the availability of the highly effective third-generation TKIs osimertinib and lorlatinib, respectively. Despite their marked efficacy, resistance to these agents remains an unsolved fundamental challenge. Both ‘on-target’ mechanisms (largely mediated by acquired resistance mutations in the kinase domains of EGFR or ALK) and ‘off-target’ mechanisms of resistance (mediated by non-target kinase alterations such as bypass signalling activation or phenotypic transformation) have been identified in patients with disease progression on osimertinib or lorlatinib. A growing understanding of the biology and spectrum of these mechanisms of resistance has already begun to inform the development of more effective therapeutic strategies. In this Review, we discuss the development of third-generation EGFR and ALK inhibitors, predominant mechanisms of resistance, and approaches to tackling resistance in the clinic, ranging from novel fourth-generation TKIs to combination regimens and other investigational therapies.

Key points

  • Non-small-cell lung cancers (NSCLCs) harbouring oncogenic EGFR mutations or ALK rearrangements can be effectively treated with EGFR and ALK tyrosine kinase inhibitors (TKIs), respectively.

  • The third-generation EGFR TKI osimertinib and the ALK TKI lorlatinib are currently the most advanced and effective clinically approved agents in their respective NSCLC subsets; both agents are highly effective including against central nervous system metastases.

  • Resistance to third-generation EGFR or ALK TKIs can be mediated by acquired EGFR or ALK kinase-domain mutations, respectively; fourth-generation TKIs designed to overcome this on-target resistance are currently in development.

  • Off-target resistance to third-generation EGFR and ALK TKIs is more prevalent than on-target resistance and is mediated by various mechanisms, including the activation of bypass signalling or phenotypic transformation.

  • Novel approaches designed to overcome resistance beyond fourth-generation TKIs, including combination therapies, antibody–drug conjugates, bispecific antibodies and immune-directed approaches, are at various stages of clinical investigation.

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Fig. 1: Timeline of genomic discoveries and drug development in EGFR-mutant and ALK-rearranged NSCLCs.
Fig. 2: Mechanisms of acquired resistance to osimertinib and lorlatinib in EGFR-mutant and ALK-rearranged NSCLCs, respectively.

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Acknowledgements

We would like to acknowledge the myriad research groups that have contributed to advances in EGFR-mutant and ALK-rearranged lung cancers, including those whose important work was not able to be featured in this Review owing to space constraints. We thank the patients, their families and clinical trial teams whose generosity and dedication have enabled drug development and advances in the mechanistic understanding of drug resistance.

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  1. Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, USA

    Alissa J. Cooper, Lecia V. Sequist & Jessica J. Lin

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All authors made a substantial contribution to all aspects of the preparation of this manuscript.

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Correspondence to Jessica J. Lin.

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L.V.S. has acted as a consultant of AstraZeneca, Genentech, Janssen, Pfizer and Takeda, and has received institutional research support from AstraZeneca, Boehringer–Ingelheim, Delfi and Novartis. J.J.L. has acted as a consultant for Bayer, Blueprint Medicines, C4 Therapeutics, Elevation Oncology, Genentech, Mirati Therapeutics, Novartis, Nuvalent and Turning Point Therapeutics, has received honoraria and travel support from Pfizer, has received institutional research funds from Bayer, Elevation Oncology, Hengrui Therapeutics, Linnaeus, Neon Therapeutics, Novartis, Nuvalent, Relay Therapeutics, Roche and Turning Point Therapeutics, and has received CME funding from MedStar Health, Northwell Health and OncLive. A.J.C. declares no competing interests.

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Nature Reviews Clinical Oncology thanks R. Rosell, N. Yamamoto, Federico Cappuzzo and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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Cooper, A.J., Sequist, L.V. & Lin, J.J. Third-generation EGFR and ALK inhibitors: mechanisms of resistance and management. Nat Rev Clin Oncol 19, 499–514 (2022). https://doi.org/10.1038/s41571-022-00639-9

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