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Unresectable stage III non-small-cell lung cancer: state of the art and challenges

Nature Reviews Clinical Oncology (2025)Cite this article

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Abstract

Despite advances in immunotherapy, unresectable stage III non-small-cell lung cancer (NSCLC) remains a highly challenging disease, with only around one-third of patients remaining disease-free at 5 years. The PACIFIC trial established consolidation with the anti-PD-L1 antibody durvalumab after concurrent chemoradiotherapy as the standard-of-care approach. Furthermore, the LAURA trial has redefined the treatment of patients with stage III unresectable EGFR-mutant NSCLC, demonstrating unprecedented progression-free survival durations with osimertinib consolidation. Despite these advances, novel approaches are urgently needed. Circulating tumour DNA-based monitoring of minimal residual disease is emerging as a personalized method of tailoring treatment duration and escalation strategies. Novel radiotherapy techniques have the potential to provide synergy with immunotherapy while minimizing toxicities. Additionally, ongoing trials evaluating chemoimmunotherapy combinations adapted from the neoadjuvant setting with the potential for conversion to resectable disease might, in the near future, redefine the boundary of surgical resectability. In this Review, we describe the rapidly evolving field of unresectable stage III NSCLC, providing a state-of-the-art overview that includes challenging topics such as biomarkers, personalization of therapy and the role of immunotherapy rechallenge.

Key points

  • The PACIFIC regimen, comprising concurrent chemoradiotherapy followed by consolidation with the anti-PD-L1 antibody durvalumab, remains the standard-of-care treatment for patients with unresectable EGFR and ALK wild-type stage III non-small-cell lung cancer (NSCLC).

  • In patients with stage III unresectable EGFR-mutant NSCLC, consolidation with a third-generation EGFR tyrosine kinase inhibitor improves progression-free survival and reduces the risk of central nervous system progression.

  • Current data do not support the addition of an immune-checkpoint inhibitor to concurrent chemoradiotherapy owing to the increased risk of toxicities as well as limited evidence of improved efficacy.

  • Limited data are available on the efficacy of induction chemoimmunotherapy in patients with unresectable stage III NSCLC, although prospective data from large-cohort phase III trials will be needed before implementation in clinical practice.

  • Strategies for patients with unresectable stage III NSCLC who are ineligible for chemotherapy are being explored in phase II trials.

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Fig. 1: Summary of treatment approaches tested in ongoing or completed trials involving patients with unresectable stage III non-small-cell lung cancer.
Fig. 2: Progression-free survival outcomes from selected trials testing consolidation immune-checkpoint inhibitors in patients with unresectable stage III non-small-cell lung cancer.
Fig. 3: Progression-free survival outcomes from selected studies testing concurrent immune-checkpoint inhibitors plus chemoradiotherapy in patients with unresectable stage III non-small-cell lung cancer.
Fig. 4: Unmet clinical challenges associated with consolidation treatment in patients with unresectable stage III non-small-cell lung cancer.

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Authors and Affiliations

  1. Department of Cancer Medicine, Gustave Roussy, Villejuif, France

    Jordi Remon

  2. Department of Radiation Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France

    Antonin Levy

  3. INSERM U1030, Gustave Roussy, Université Paris-Saclay, Villejuif, France

    Antonin Levy

  4. Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicetre, Paris, France

    Antonin Levy

  5. Department of Medical Oncology, Centre Léon Bérard, Lyon, France

    Romane Gille & Maurice Pérol

  6. Department of Radiotherapy, Centre Léon Bérard, Lyon, France

    Isabelle Martel-Lafay

  7. Department of Pulmonary Diseases, Maastricht University Medical Centre (+), GROW Research Institute for Oncology and Reproduction, Maastricht, The Netherlands

    Martina Bortolot & Lizza E. L. Hendriks

  8. Department of Medicine (DMED), University of Udine, Udine, Italy

    Martina Bortolot

  9. Radiotherapy Related Research, University of Manchester and The Christie NHS Foundation, Manchester, UK

    Corinne Faivre-Finn

  10. Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada

    Natasha Leighl

  11. Airway Research Center North, German Center of Lung Research, Lung Clinic, Grosshansdorf, Germany

    Martin Reck

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Contributions

J.R., R.G. and M.B. researched data for the manuscript, J.R., A.L., R.G., I.M.-L., M.B., L.E.L.H., C.F.-F. and M.P. wrote the manuscript, J.R., C.F.-F., M.R. and M.P. made a substantial contribution to discussions of content and all authors reviewed and/or edited the manuscript before submission.

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Correspondence to Jordi Remon.

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Competing interests

J.R. has acted as a consultant and/or adviser of AstraZeneca, Johnson & Johnson and Regeneron, has acted as a speaker for AstraZeneca, Johnson & Johnson, Roche and Sanofi, has received research funding from AstraZeneca, Merck and MSD, has received travel support from MSD and Ose Immunotherapeutics and is the chair of EORTC-LCG and a member of the editorial boards of the Journal of Clinical Oncology, Lung Cancer and Journal of Thoracic Oncology. A.L. has received research funding from AstraZeneca, Beigene, MSD, Pharmamar and Roche. L.E.L.H. has acted as a consultant and/or adviser of Abbvie, Amgen, Anhearth, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Daiichi, Gilead, GSK, Janssen, Lilly, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, Summit Therapeutics and Takeda, has acted as a speaker for AstraZeneca, Bayer, Benecke, GSK, Janssen, high5oncology, Lilly, Medimix, Medtalks, MSD, Pfizer, Sanofi, Takeda and VJOncology, has received research funding from Amgen, AstraZeneca, Boehringer Ingelheim, Gilead, Merck, Novartis, Pfizer and Takeda and has acted as a guideline committee member for the Dutch guidelines on NSCLC, brain metastases and leptomeningeal metastases, the ESMO guidelines on metastatic NSCLC, non-metastatic NSCLC and SCLC, is the former secretary and current chair of the NVALT Studies Foundation, is the former subchair and current secretary of the EORTC Metastatic NSCLC Systemic Therapy Group and the vice-chair of the scientific committee of the Dutch Thoracic Group. M.P. has acted as a consultant and/or adviser of Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Gilead Sciences, GlaxoSmithKline, Ipsen, Janssen Oncology, Lilly, Merck Sharp & Dohme, Novartis, Novocure, Pfizer, Roche/Genentech, Sanofi and Takeda, has received research funding from Takeda, has received travel support from AstraZeneca, Chugai Pharma, Bristol Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche and Takeda and is a member of the editorial board of the Journal of Clinical Oncology. The other authors declare no competing interests.

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Nature Reviews Clinical Oncology thanks T. Cascone, R. Dziadziuszko, S. Ramalingam, and J.C.H. Yang for their contribution to the peer review of this work.

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Remon, J., Levy, A., Gille, R. et al. Unresectable stage III non-small-cell lung cancer: state of the art and challenges. Nat Rev Clin Oncol (2025). https://doi.org/10.1038/s41571-025-01080-4

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