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Evolution of systemic therapy for stages I–III non-metastatic non-small-cell lung cancer

Abstract

The treatment goal for patients with early-stage lung cancer is cure. Multidisciplinary discussions of surgical resectability and medical operability determine the modality of definitive local treatment (surgery or radiotherapy) and the associated systemic therapies to further improve the likelihood of cure. Trial evidence supports cisplatin-based adjuvant therapy either after surgical resection or concurrently with radiotherapy. Consensus guidelines support neoadjuvant chemotherapy in lieu of adjuvant chemotherapy and carboplatin-based regimens for patients who are ineligible for cisplatin. The incorporation of newer agents, now standard for patients with stage IV lung cancer, into the curative therapy paradigm has lagged owing to inefficient trial designs, the lengthy follow-up needed to assess survival end points and a developmental focus on the advanced-stage disease setting. Surrogate end points, such as pathological response, are being studied and might shorten trial durations. In 2018, the anti-PD-L1 antibody durvalumab was approved for patients with stage III lung cancer after concurrent chemoradiotherapy. Since then, the study of targeted therapies and immunotherapies in patients with early-stage lung cancer has rapidly expanded. In this Review, we present the current considerations in the treatment of patients with early-stage lung cancer and explore the current and future state of clinical research to develop systemic therapies for non-metastatic lung cancer.

Key points

  • Cisplatin-based adjuvant chemotherapy remains the standard of care for patients with resected high-risk non-metastatic non-small-cell lung cancer (NSCLC).

  • Anti-PD-L1 therapy with durvalumab after concurrent chemotherapy and radiotherapy for unresectable or inoperable non-metastatic NSCLC improves overall survival.

  • Osimertinib for 3 years after standard adjuvant therapy improves disease-free survival in patients with NSCLC harbouring EGFR mutations.

  • Immunotherapy is being extensively studied in the preoperative and postoperative settings.

  • Novel clinical trial designs are needed to accelerate advances in the treatment of patients with curable NSCLC.

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Fig. 1: Treatment of metastatic and non-metastatic NSCLC.
Fig. 2: Graphic depiction of a definitive proton radiotherapy dose distribution in a patient with stage IIIC non-small-cell lung cancer.

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Acknowledgements

We would like to thank C. Wilhelm for critically reading the manuscript and for editorial contributions and A. F. Shepherd for contributions to Fig. 2. The work of the authors is supported in part by an NIH grant P30 CA008748 to Memorial Sloan Kettering Cancer Center. T.C. is the recipient of an ASCO Career Development Award and her work is partially supported by the NIH grant P30 CA016672 to the University of Texas MD Anderson Cancer Center.

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All authors researched data for the article, made substantial contributions to discussions of content, wrote the manuscript, and reviewed and edited the manuscript before submission.

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Correspondence to Jamie E. Chaft.

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J.E.C. reports consulting fees from AstraZeneca, Bristol–Myers Squibb, Flame Biosciences, Genentech, Merck, and Novartis and clinical research funding to Memorial Sloan Kettering Cancer Center from AstraZeneca, Bristol–Myers Squibb, Genentech and Merck. A.R. reports grants from Boehringer Ingelheim, Pfizer, and Varian Medical Systems, grants and personal fees from AstraZeneca and Merck, personal fees from Cybrexa, More Health and Research to Practice, and non-financial support from Philips–Elekta, outside the submitted work. W.W. reports advisory board and speaker fees from AstraZeneca as well as teaching grant and speaker fees from Covidien–Medtronic. M.G.K. reports personal fees from AstraZeneca, Daiichi–Sankyo, Pfizer and Regeneron from outside the submitted work and honoraria for participation in educational programmes from AstraZeneca, AXIS, Carvive Systems, Creative Educational Concepts, i3 Health, Intellisphere, OncLive, Paradigm Medical Communications, Peerview, Physicians Education Resources, Prime Oncology, Research to Practice and WebMD. Funds for travel and lodging as well as food and beverage have been provided by AstraZeneca, Genentech, Pfizer and Regeneron. M.G.K. is an employee of Memorial Sloan Kettering. Memorial Sloan Kettering has received research funding from Genentech Roche, the Lung Cancer Research Foundation, the US National Cancer Institute and PUMA Biotechnology for research conducted by M.G.K. Memorial Sloan Kettering has licensed testing for EGFR T790M to MolecularMD. T.C. reports consulting fees from Bristol–Myers Squibb and MedImmune–AstraZeneca, advisory role fees from Bristol–Myers Squibb and EMD Serono, and clinical research funding to MD Anderson Cancer Center from Boehringer Ingelheim, Bristol–Myers Squibb, EMD Serono, and MedImmune–AstraZeneca. C.G.A. declares no competing interests.

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Chaft, J.E., Rimner, A., Weder, W. et al. Evolution of systemic therapy for stages I–III non-metastatic non-small-cell lung cancer. Nat Rev Clin Oncol 18, 547–557 (2021). https://doi.org/10.1038/s41571-021-00501-4

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