Immunotherapy with checkpoint inhibitors in non-small cell lung cancer: insights from long-term survivors

  • Ernest NadalEmail author
  • Bartomeu Massuti
  • Manuel Dómine
  • Rosario García-Campelo
  • Manuel Cobo
  • Enriqueta Felip


Immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 (PD-1)–programmed cell death ligand-1 (PD-L1) axis have shown promising results in non-small cell lung cancer (NSCLC) patients, some of them with persistent responses to these agents that form a population of long-term survivors. Despite the variable definition of PD-L1 positivity in tumors, an association between expression and response has been reasonably consistent in advanced NSCLC. In addition, the clinical efficacy of ICIs seems to be related to the genomic landscape of the tumor in terms of mutational burden and clonal neoantigens. Furthermore, increasing evidence shows that excessive activation of the immune response elicited by ICIs, leading to immune-related toxicities, might be associated with an improved response to immunotherapy. There are still many unanswered questions about the proper use of these agents to maximize their efficacy, which may be improved through combination with radiation, chemotherapy, targeted therapies, or other immune mediators, including dual checkpoint blockade. To search for clues for addressing these challenges, this review focused on the characteristics and clinical features of long-term NSCLC survivors and the potential biomarkers of response to ICIs.


Biomarker Immune checkpoint inhibitors Immunotherapy Long-term survival Non-small cell lung cancer PD-L1 



Adverse event


American Society of Clinical Oncology


Confidence intervals


Hazard ratio


Immune checkpoint inhibitor




immune-related adverse event


Lactate dehydrogenase


Lung Immune Prognostic Index




Neutrophil to lymphocyte ratio




Non-small cell lung cancer


Overall response rate


Progression-free survival




Tumor mutation burden


Tumor microenvironment


Tumor necrosis factor



The authors would like to thank Anabel Herrero, on behalf of Springer Healthcare, for assistance in the preparation of the manuscript, and Catherine Rees, of Springer Healthcare communications, for revising the manuscript based on peer review comments.

Author contributions

EN drafted the manuscript, coordinated the different contributions, reviewed evidence and wrote the first draft of the section “Biomarkers and long-term survival”. BM reviewed evidence and wrote the first draft of the section “Characteristics of long-term NSCLC survivors treated with ICIs”. MD reviewed evidence and wrote the first draft of the section “Relationship between toxicity and benefit of ICIs”. RGC reviewed evidence and wrote the first draft of the section “Current and future therapeutic combinations”. MC reviewed evidence and wrote the first draft of the section “Long-term survival in NSCLC patients treated with ICIs”. EF coordinated the “Introduction” and “Concluding remarks”, as well as the different authors’ contributions with EN. All authors reviewed and approved the final manuscript version.


Medical writing assistance was funded by Bristol-Myers Squibb. Ernest Nadal has received a grant from the Department of Health of the Generalitat de Catalunya (SLT006/17/00127). The authors would like to thank CERCA Programme/Generalitat de Catalunya for institutional support.

Compliance with ethical standards

Conflict of interest

Ernest Nadal has received honoraria for participating in advisory boards and speaking honorarium from Bristol-Myers Squibb, Merck Sharp & Dohme, Roche, Pfizer, Takeda, Boehringer Ingelheim and AstraZeneca. Bartomeu Massuti has received honoraria for participation in advisory boards and speaking from Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Serono, Merck Sharp & Dohme, Pfizer, and Roche. Manuel Dómine declares that he has no conflict of interest. Rosario García-Campelo has received honoraria for participation in advisory boards and speaking from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, and Takeda. Manuel Cobo has received speaker honorarium from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, and Roche. Enriqueta Felip has received honoraria for participation in advisory boards and speaking from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, GuardantHealth, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda.


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© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Medical OncologyCatalan Institute of Oncology (ICO)BarcelonaSpain
  2. 2.Clinical Research in Solid Tumors (CReST) Group, OncoBell ProgramIDIBELLBarcelonaSpain
  3. 3.Department of Medical OncologyHospital Universitario de Alicante, ISABIALAlicanteSpain
  4. 4.Department of Medical OncologyHospital Universitario Fundación Jiménez Díaz, Oncohealth Institute, Universidad Autónoma de MadridMadridSpain
  5. 5.Department of Medical OncologyA Coruña University HospitalA CoruñaSpain
  6. 6.Medical Oncology DepartmentHospital Universitario Málaga Regional y Virgen de la Victoria, IBIMAMálagaSpain
  7. 7.Lung Cancer UnitHospital Universitari Vall d’Hebron and Vall d’Hebron Institute of Oncology (VHIO)BarcelonaSpain

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