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Review
. 2025 May;22(5):371-378.
doi: 10.1038/s41571-025-01011-3. Epub 2025 Mar 14.

Utilizing ctDNA to discover mechanisms of resistance to targeted therapies in patients with metastatic NSCLC: towards more informative trials

Sophie M Ernst  1 , Mihaela Aldea  2   3   4 , Jan H von der Thüsen  5 , Adrianus J de Langen  6 , Egbert F Smit  7 , Marthe S Paats  1 , Joachim G J V Aerts  1 , Laura Mezquita  8   9 , Sanjay Popat  10 , Benjamin Besse  2   3 , Jordi Remon  2 , Christian Rolfo  11 , Hendrikus J Dubbink  5 , Anne-Marie C Dingemans  12
Affiliations
Review

Utilizing ctDNA to discover mechanisms of resistance to targeted therapies in patients with metastatic NSCLC: towards more informative trials

Sophie M Ernst et al. Nat Rev Clin Oncol. 2025 May.

Abstract

Advances in targeted therapies for patients with non-small-cell lung cancer have substantially improved the outcomes of those with actionable alterations in certain oncogenic driver genes. However, acquired resistance to these targeted therapies remains a major challenge. Understanding the mechanisms underlying acquired resistance will be crucial for the development of strategies that might either overcome this effect or delay the onset. Circulating tumour DNA, owing to the need for only minimally invasive sampling and a potential role as both a prognostic and predictive biomarker, is increasingly being used in both research and clinical practice. Several studies have explored the landscape of acquired resistance to targeted therapies using this approach. However, the methodologies of the published studies vary widely, and several major challenges remain in addressing the practical difficulties associated with these methods. These challenges currently limit the depth of research insight provided by the available data. In this Perspective, we review clinical reports describing the use of circulating tumour DNA to detect mechanisms of acquired resistance to targeted therapies, predominantly in patients with advanced-stage non-small-cell lung cancer, and highlight key unresolved questions with the aim of moving towards more-informative research studies.

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Conflict of interest statement

Competing interests: M.A. has received research funding from Amgen, AstraZeneca and Sandoz. A.J.d.L. has acted as a consultant of AstraZeneca, BMS, Boehringer Ingelheim, Daiichi/Sankyo, Lilly, MSD and Pfizer and received research funding from AstraZeneca, BMS, Boehringer Ingelheim and MSD. E.F.S. has acted as a consultant of AstraZeneca, BMS, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Janssen, Merck, MSD, Roche, Sanofi and Takeda, acted as a speaker for Boehringer Ingelheim, Daiichi Sankyo and participated in Data and Safety Monitoring Boards for DSI, Mythis and Taiho. M.S.P. has acted as a consultant and/or adviser of Amgen, Eli Lilly, Janssen, Merck and Pfizer. J.G.J.V.A. has acted as a consultant of AstraZeneca, CureVac, Danone and MSD, has acted as a speaker on behalf of BMS, Eli Lilly and MSD, has received research funding from AstraZeneca, Danone and Genmab, is listed on patents relating to allogenic tumour cell lysates, combination immune-oncology drug regimens and biomarkers for immunotherapy, has unpaid leadership roles as Treasurer of the IASLC and is a board member of IMIG and holds stock options in Amphera. L.M. has acted as a consultant of Janssen, MSD+, Roche and Takeda, has acted as a speaker for AstraZeneca, Janssen, MSD, Pfizer, Radonova, Roche and Takeda, has received research funding from Amgen, AstraZeneca, Gilead and Inivata and received travel support from AstraZeneca, BMS, Janssen, Roche and Takeda. S.P. has acted as a consultant of Anhaert Therapeutics, Amgen, Arcus Biosciences, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Daiichi Sankyo, Ellipses, Erasca, Gilead, GSK, Guardant Health, IO Biotech, Janssen, Lilly, Merck KGaA, Mirati, MSD, Novocure, Novartis, Pfizer, Pharmamar, Pierre Fabr, Regeneron, Roche, Sanofi, Takeda and Turning Point Therapeutics, received speaker’s fees from Amgen, AstraZeneca, Bayer, Gilead, Guardant Health, Janssen, Merck KGaA, Novocure, Pharmamar, Pfizer, Roche and Takeda, received travel support from Gilead and has unpaid leadership roles in ALK positive UK, BTOG, ETOP/IBCSG Foundation Board, Lung Cancer Europe, Mesothelioma Applied Research Foundation and Ruth Strauss Foundation. B.B. has acted as a consultant and/or adviser of Abbvie, Amgen, AstraZeneca, Biontech SE, Beigene, Beijing Avistone Biotechnology, BMS, CureVac AG, Eli Lilly, Ellipses pharma, F. Hoffmann-La Roche, Foghorn Therapeutics, Genmab, Immunocore, Janssen, Pharmamar, MSD, Ose Immunotherapeutics, Owkin, Regeneron, Sanofi Aventis and Takeda and has acted as a speaker for Abbvie, AstraZeneca, BMS, Daichii Sankyo, Lilly, MSD, Ose Immunotherapeutics, Sanofi Aventis and Servier. J.R. has acted as a speaker for Johnson & Johnson and MSD, has received travel support from MSD and has an unpaid leadership role as Secretary of the EORTC lung cancer group. C.R. has acted as a consultant of Abbvie, ACC MED, ASCO Plenary Series, Amgen, Bayer, Blueprint, Cadence, Diverse Health Hub, Eisai, GME, Guardant Health, Invitae, Janssen Scientific Affairs, Lungevity, Medical Educator Consortium, Merck, MSHO, MH Live Events, Nadirex, Novartis, Novocure, Regeneron and Thermo Fisher, has acted as a speaker for AstraZeneca, Aptitude Health, Boehringer Ingelheim, COR2ED, Intellisphere LLC, IDEOLogy, MSD and Roche and has received research funding from Pfizer and Roche. H.J.D. has acted as an adviser of Abbvie, Astellas, AstraZeneca, Janssen and MSD and has acted as a speaker for AstraZeneca, BMS, GSK, Illumina, Johnson & Johnson, MSD and Roche, has received research funding from AstraZeneca, HederaDx, Illumina, MSD and OncoDNA. A.-M.C.D. has acted as an adviser and/or consultant of Abbvie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi, Eli Lilly, Johnson & Johnson, Mirati, Pfizer and Roche and has acted as a speaker for Amgen, Eli Lilly and Johnson & Johnson, has participated in Independent Data Monitoring Committees for Roche and Takeda and has an unpaid leadership role as chair of the EORTC lung cancer group. The other authors declare no competing interests.

References

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