For patients with metastatic non–small-cell lung cancer (mNSCLC), the last decade has been characterized by critical progress that has contributed to substantially improved survival. In particular, the development of specific antibodies against the programmed death (PD-1) receptor, programmed death-ligand 1 (PD-L1), and the cytotoxic T-lymphocyte–associated protein 4 receptor in the therapeutic strategy of mNSCLC either in first- or in second-line settings have led to unprecedented prolonged survival for a proportion of these patients. Although clinical development of immune checkpoint inhibitors with anti–PD-1 and PD-L1 therapies largely began as monotherapy in the second-line setting, the more recent progress has shifted toward combination approaches in first-line settings as well as the integration of immunotherapy into the clinical paradigm in earlier stages. Today, with the exception of mNSCLC harboring targetable oncogenes, nearly all patients with mNSCLC receive PD-1 or PD-L1 therapy in first-line settings. Here we report the current status of first-line immunotherapy in mNSCLC together with current challenges in selecting the best immunotherapeutic approach for the individual patient.

© 2022 by American Society of Clinical Oncology

  • Key Objective

  • The implementation of immunotherapies with checkpoint inhibitors has substantially improved therapeutic outcomes of patients with advanced or metastatic non–small-cell lung cancer (NSCLC). In the recent years, different monotherapies as well as different combinations have been reported and approved, which require a clinical interpretation and patient-related assignment.

  • Knowledge Generated

  • A current overview on the different treatment opportunities based on the most recent treatment trial reports provides insights into the complex and evolving field of first-line immunotherapies in nononcogenic addicted metastatic NSCLC. Additional results of translational biomarker analyses and clinical considerations of relevant treatment decisions support the transition from clinical trial outcomes to daily practice reality. A concluding outlook on ongoing research and trial concepts offers a view on the promising perspective of immunotherapy in NSCLC.

  • Relevance

  • This overview might help the clinical oncologist in the treatment decision and selection of the most appropriate immunotherapy or immunotherapy combination for his patients with metastatic NSCLC.

Conception and design: Martin Reck, Jordi Remon, Matthew D. Hellmann

Collection and assembly of data: All authors

Data analysis and interpretation: Jordi Remon, Matthew D. Hellmann

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

First-Line Immunotherapy for Non–Small-Cell Lung Cancer

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Martin Reck

Consulting or Advisory Role: Lilly, MSD Oncology, Merck Serono, Bristol Myers Squibb, AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Roche/Genentech, AbbVie, Amgen, Mirati Therapeutics, Samsung Bioepis, Sanofi/Regeneron

Speakers' Bureau: Roche/Genentech, Lilly, MSD Oncology, Merck Serono, Bristol Myers Squibb, AstraZeneca, Boehringer Ingelheim, Celgene, Pfizer, Novartis, Amgen, Mirati Therapeutics, Sanofi/Aventis

Jordi Remon

Consulting or Advisory Role: Pfizer, Bristol Myers Squibb, Boehringer Ingelheim, MSD Oncology, AstraZeneca, OSE Immunotherapeutics

Travel, Accommodations, Expenses: Roche/Genentech, Inivata, OSE Immunotherapeutics, AstraZeneca

Matthew D. Hellmann

Stock and Other Ownership Interests: Shattuck Labs, Immunai, Arcus Biosciences, Shattuck Labs, Factorial

Consulting or Advisory Role: Bristol Myers Squibb, Merck, Genentech, AstraZeneca/MedImmune, Mirati Therapeutics, Immunai, Blueprint Medicines, Natera, Shattuck Labs, Arcus Biosciences, Achilles Therapeutics, Adagene, Adicet Bio, Lilly, Janssen, Instil Bio, Mana Therapeutics, PACT Pharma, Regeneron

Research Funding: Bristol Myers Squibb

Patents, Royalties, Other Intellectual Property: A patent has been filed by Memorial Sloan Kettering (PCT/US2015/062208) for the use of tumor mutation burden for prediction of immunotherapy efficacy, and which is licensed to Personal Genome Diagnostics

No other potential conflicts of interest were reported.




DOI: 10.1200/JCO.21.01497 Journal of Clinical Oncology 40, no. 6 (February 20, 2022) 586-597.

Published online January 05, 2022.

PMID: 34985920

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