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  • Review Article
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Immune-checkpoint inhibition for resectable non-small-cell lung cancer — opportunities and challenges

Nature Reviews Clinical Oncology volume 20, pages 664–677 (2023)Cite this article

Subjects

Abstract

Therapeutic strategies harnessing the immune system to eliminate tumour cells have been successfully used for several cancer types, including in patients with advanced-stage non-small-cell lung cancer (NSCLC). In these patients, immune-checkpoint inhibitors (ICIs) can provide durable responses and improve overall survival either as monotherapy, or combined with chemotherapy or other immunotherapeutic agents. However, the implementation of ICIs in early stage NSCLC has been hampered by the continuous struggle to develop robust end points to assess their efficacy in this setting, especially those enabling a fast and reproducible evaluation of the clinical activity of neoadjuvant strategies. Several trials are testing ICIs, alone or in combination with chemotherapy, in early stage NSCLC as an adjuvant, neoadjuvant or perioperative approach. As a novelty, most trials in the neoadjuvant setting have adopted pathological response as a primary end point. ICIs have been approved for use in the neoadjuvant and adjuvant settings on the basis of event-free survival and disease-free survival benefit, respectively; however, the correlation of these end points with overall survival remains unclear in these settings. Unresolved challenges for the optimal use of ICIs with curative intent include concerns about their applicability in daily clinical practice and about improving patient selection based on predictive biomarkers or assessment of pathological response and minimal residual disease. In this Review, we discuss the rationale, available strategies and current trial landscape for the implementation of ICIs in patients with resectable NSCLC, and we further elaborate on future approaches to optimize their clinical benefit.

Key points

  • Preoperative, postoperative and perioperative treatment with immune-checkpoint inhibitors (ICIs) can be exploited therapeutically to maximize clinical outcomes in patients with resectable (stage I–IIIA/B) non-small-cell lung cancer (NSCLC).

  • In patients with resectable NSCLC, the addition of nivolumab to neoadjuvant platinum-doublet chemotherapy significantly increases pathological response rates and prolongs event-free survival.

  • In patients with PD-L1-positive resected stage II–IIIA NSCLC, adjuvant treatment with atezolizumab or pembrolizumab after platinum-based chemotherapy significantly prolongs disease-free survival.

  • Perioperative chemoimmunotherapy with ICIs such as durvalumab, toripalimab and pembrolizumab significantly increases pathological response rates and prolongs event-free survival.

  • Determination of optimal combinations, sequence and duration of ICI treatment, as well as the identification of robust biomarkers and end points in both the neoadjuvant and adjuvant settings, remain important challenges.

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Fig. 1: Biological rationale for ICI-based treatment of patients with resectable non-small-cell lung cancer.
Fig. 2: Clinical trials of neoadjuvant and perioperative ICIs in resectable non-small-cell lung cancer.
Fig. 3: Ongoing clinical trials of adjuvant immune-checkpoint inhibitors in resectable non-small-cell lung cancer.
Fig. 4: Neoadjuvant versus adjuvant treatment with immune-checkpoint inhibitors in patients with resectable non-small-cell lung cancer.

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Acknowledgements

G.M. dedicates this work to his father, who died of cancer during the preparation of this Review.

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Author notes

  1. Τhese authors contributed equally: Giannis Mountzios, Jordi Remon.

Authors and Affiliations

  1. Fourth Department of Medical Oncology and Clinical Trials Unit, Henry Dunant Hospital Center, Athens, Greece

    Giannis Mountzios

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

    Jordi Remon & Benjamin Besse

  3. Department of Respiratory Medicine, Maastricht University Medical Centre, GROW School for Oncology and Reproduction, Maastricht, Netherlands

    Lizza E. L. Hendriks

  4. Department of Medical Oncology, Hospital Universitario A Coruña, A Coruña, Spain

    Rosario García-Campelo

  5. Center for Thoracic Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Christian Rolfo

  6. Department of Thoracic and Vascular Surgery, University Hospital of Antwerp, Antwerp, Belgium

    Paul Van Schil

  7. Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA

    Patrick M. Forde

  8. Department of Cancer Medicine, Université Paris-Saclay, Orsay, France

    Benjamin Besse & Jean-Charles Soria

  9. Department of Cancer Medicine, Sarah Cannon Research Institute, Nashville, TN, USA

    Vivek Subbiah

  10. Department of Thoracic Oncology, Airway Research Center North, German Center of Lung Research, Lung Clinic, Grosshansdorf, Germany

    Martin Reck

  11. Oncology Department, CHUV, Lausanne University, Lausanne, Switzerland

    Solange Peters

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Contributions

G.M., J.R., L.E.L.H., R.G.-C. and S.P. contributed substantially to discussion of contents. All the authors researched data for the article, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Giannis Mountzios.

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Competing interests

G.M. has acted as an adviser and/or consultant for Amgen, AstraZeneca, BMS, GSK, MSD, Novartis, Pfizer, Roche, Sanofi and Takeda; has received travel and accommodation fees from Amgen, AstraZeneca, BMS, GSK, Ipsen, MSD, Novartis, Roche, Sanofi and Takeda; and has been a principal investigator in clinical trials sponsored by Amgen, AstraZeneca, BMS, Gilead, GSK, Ιmmunomedics, Merck, MSD, Novartis, Roche and Sanofi. J.R. has acted as an adviser for Bayer, BMS, Boehringer Ingelheim, GenMab, Janssen, MSD and Takeda; has received speaker fees from Janssen and Pfizer; has received honoraria from MSD; and has received travel fees from AstraZeneca, BMS, OSE Immunotherapeutics and Roche. L.E.L.H. has received speaker fees from Benecke, Medtalks and VJOncology; has received personal fees from the committee that revised the Dutch guidelines on non-small-cell lung cancer, brain metastases and leptomeningeal metastases, AstraZeneca, Janssen and Roche; has received institutional fees from Amgen, AstraZeneca, Bayer, Beigene, BMS, Boehringer Eli Lilly, Ingelheim, high5oncology, Janssen, Merck, MSD, Novartis, Pfizer, Roche and Takeda; has received institutional research grants from AstraZeneca, Boehringer Ingelheim, Merck, Pfizer, Roche and Takeda; and has received institutional funding as a local principal investigator from AbbVie, AstraZeneca, Blueprint Medicines, Gilead, GSK, Merck Serono, Mirati, MSD, Novartis, Roche and Takeda. R.G.-C. has acted as an adviser and/or consultant for AstraZeneca, BMS, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi and Takeda; has received speaker fees from AstraZeneca, BMS, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi and Takeda; and has received research funding from BMS. C.R. has received consulting fees from Archer, Bayer, Boston Pharmaceuticals, Daiichi Sankyo, Eisai, EMD Serono, General Dynamics, Inviata, Janssen, Mirati, Novartis, Pfizer and Sanofi; has had stock options from Novartis; has been in the speaker’s bureau of AstraZeneca, COR2D, Guardanthealth, Intellisphere, MSD, Physician’s Education Resource, LLC and Roche; has received grant support from Pfizer; and has participated in the safety monitoring board of EMD Serono. P.V.S. is an adviser and/or has received honoraria for lectures from AstraZeneca, BMS, Janssen, MSD and Roche. P.M.F. receives institutional research funding from AstraZeneca, BMS, Corvus, Kyowa, Novartis and Regeneron; has been a consultant for Amgen, AstraZeneca, BMS, Daiichi, F-Star, G1, Roche Genentech, Janssen, Iteos, Merck, Novartis, Sanofi and Surface; and is a member of the data and safety monitoring board at Polaris. B.B. receives institutional grants from Abbvie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, Ipsen, Merck, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda and Tiziana Pharma. V.S. receives research funding and/or grant support for clinical trials from AbbVie, Agensys, Alfasigma, Altum, Amgen, Bayer, BERG Health, Blueprint Medicines, Boston Biomedical, Boston Pharmaceuticals, Celgene, D3 Bio, Dragonfly Therapeutics, Exelixis, Fujifilm, GSK, Idera Pharmaceuticals, Incyte Corporation, Inhibrx, Loxo Oncology, MedImmune, MultiVir, NanoCarrier, Northwest Biotherapeutics, Novartis, PharmaMar, Pfizer, Relay Therapeutics, Roche/Genentech, Takeda, Turning Point Therapeutics and Vegenics; has received travel support from Helsinn Healthcare, Incyte Corporation, Novartis and PharmaMar; has acted as a consultant and/or adviser for Eli Lilly, Helsinn Healthcare, Jazz Pharmaceuticals,  Incyte Corporation, Loxo Oncology, MedImmune, Novartis, QED Therapeutics, Relay Therapeutics, Daiichi-Sankyo and R-Pharm; and has other relationships with Medscape. M.R. has received personal honoraria for lectures and consultancy from Amgen, AstraZeneca, Beigene, BMS, Boehringer Ingelheim, Daiichi Sankyo, GSK, Elli Lilly, Merck, Mirati, MSD, Novartis, Pfizer, Regeneron, Roche and Sanofi; is a paid member of the data monitoring committee for Daiichi-Sankyo and Sanofi; and has received travel and accommodation fees from Amgen, AstraZeneca, Beigene, BMS, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, GSK, Merck, Mirati, MSD, Novartis, Pfizer, Regeneron, Roche and Sanofi. J.-C.S. is a full-time employee at Amgen; and holds shares from Amgen, Gritstone Bio and Relay Therapeutics. S.P. has had consultant and/or advisory roles at AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Biocartis, BMS, Boehringer Ingelheim, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Foundation Medicine, Illumina, Imedex, Incyte, Janssen, Medscape, Merck Serono, Merrimack, MSD, Novartis, Pharma Mar, Phosplatin Therapeutics, Pfizer, Regeneron, Roche/Genentech, Sanofi, Seattle Genetics and Takeda; has been a speaker for AstraZeneca, BMS, Boehringer Ingelheim, ecancer, Eli Lilly, Illumina, Imedex, Medscape, Merck Sharp and Dohme, Novartis, Pfizer, Prime, Roche/Genentech, Sanofi and Takeda; and has received institutional grants and/or institutional financial support for clinical trials sponsored by Amgen, AstraZeneca, Biodesix, BMS, Boehringer Ingelheim, Clovis, Eli Lilly, GSK, Illumina, Merck Serono, Mirati, MSD, Novartis, Pfizer, Phosplatin Therapeutics and Roche/Genentech.

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Mountzios, G., Remon, J., Hendriks, L.E.L. et al. Immune-checkpoint inhibition for resectable non-small-cell lung cancer — opportunities and challenges. Nat Rev Clin Oncol 20, 664–677 (2023). https://doi.org/10.1038/s41571-023-00794-7

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