Immunotherapy with checkpoint inhibitors in non-small cell lung cancer: insights from long-term survivors
- 1k Downloads
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.
KeywordsBiomarker Immune checkpoint inhibitors Immunotherapy Long-term survival Non-small cell lung cancer PD-L1
American Society of Clinical Oncology
Immune checkpoint inhibitor
immune-related adverse event
Lung Immune Prognostic Index
Neutrophil to lymphocyte ratio
Non-small cell lung cancer
Overall response rate
Tumor mutation burden
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.
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.
- 18.National Cancer Institute (2017) Cancer Stat facts: lung and bronchus cancer. https://seer.cancer.gov/statfacts/html/lungb.html. Accessed 13 June 2017
- 23.Park K, Lewanski C, Gadgeel S et al. 3-year survival and duration of response in randomized phase ii study of atezolizumab vs docetaxel in 2L/3L NSCLC (POPLAR). J Thorac Oncol 12:S1840Google Scholar
- 30.Brahmer J, Horn L, Jackman D, Spigel D, Scott A, Hellmann M, Powderly J (2017) Five-year follow-up from the CA209-003 study of nivolumab in previously treated advanced non-small cell lung cancer (NSCLC): clinical characteristics of long-term survivors. http://www.abstractsonline.com/pp8/#!/4292/presentation/12343. Accessed 13 June 2017
- 33.Mansfield AS, Aubry MC, Moser JC, Harrington SM, Dronca RS, Park SS, Dong H (2016) Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer. Ann Oncol 27:1953–1958CrossRefPubMedPubMedCentralGoogle Scholar
- 42.Hellmann MD, Nathanson T, Rizvi H et al (2018) Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer. Cancer Cell 33:843 e4–852 e4Google Scholar
- 47.Labomascus S, Fughhi I, Bonomi P, Fidler MJ, Borgia JA, Basu S, Hoch MA, Batus M (2017) Neutrophil to lymphocyte ratio as predictive of prolonged progression free survival (PFS) and overall survival (OS) in patients with metastatic non-small cell lung cancer (NSCLC) treated with second-line PD-1 immune checkpoint inhibitors. J Clin Oncol 35:e14530-eCrossRefGoogle Scholar
- 49.Zer A, Sung MR, Walia P et al (2018) Correlation of neutrophil to lymphocyte ratio and absolute neutrophil count with outcomes with PD-1 axis inhibitors in patients with advanced non-small-cell lung cancer. Clin Lung Cancer 19(5):426–434.e1. https://doi.org/10.1016/j.cllc.2018.04.008 CrossRefPubMedGoogle Scholar
- 59.Costa R, Carneiro BA, Agulnik M, Rademaker AW, Pai SG, Villaflor VM, Cristofanilli M, Sosman JA, Giles FJ (2017) Toxicity profile of approved anti-PD-1 monoclonal antibodies in solid tumors: a systematic review and meta-analysis of randomized clinical trials. Oncotarget 8:8910–8920PubMedGoogle Scholar
- 61.Horvat TZ, Adel NG, Dang TO et al (2015) Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at memorial sloan kettering cancer center. J Clin Oncol 33:3193–3198CrossRefPubMedPubMedCentralGoogle Scholar
- 63.Leighl N, Gandhi L, Hellmann M et al (2015) Pembrolizumab for NSCLC: immune-mediated adverse events and corticosteroid use. J Thorac Oncol 10:S233Google Scholar
- 68.Schadendorf D, Larkin J, Postow M, Chiarion-Sileni V, Gonzalez R, Rutkowski P (2016) Efficacy and safety outcomes in patients with advanced melanoma (MEL) who discontinued treatment with nivolumab (NIVO) plus ipilimumab (IPI) due to toxicity. In: 12th Congress of the European Association of Dermato Oncology, August 31-September 3, 2016; Vienna, AustriaGoogle Scholar
- 72.von Pawel J, Syrigos K, Mazieres J et al (2017) Association between immune-related adverse events (irAEs) and atezolizumab efficacy in advanced NSCLC: analyses from the phase III study OAK. Ann Oncol 28:1314PGoogle Scholar
- 73.Haratani K, Hayashi H, Chiba Y et al (2017) Association of immune-related adverse events with nivolumab efficacy in non-small-cell lung cancer. JAMA OncolGoogle Scholar
- 76.Gerber DE, Urbanic JJ, Langer C et al (2017) Treatment design and rationale for a randomized trial of cisplatin and etoposide plus thoracic radiotherapy followed by nivolumab or placebo for locally advanced non-small-cell lung cancer (RTOG 3505). Clin Lung Cancer 18:333–339CrossRefPubMedGoogle Scholar
- 81.Borghaei H, Langer CJ, Gadgeel S et al (2017) Updated results from KEYNOTE-021 cohort G: a randomized, phase 2 study of pemetrexed and carboplatin (PC) with or without pembrolizumab (pembro) as first-line therapy for advanced nonsquamous NSCLC. Ann Oncol 28:LBA49Google Scholar
- 90.Planchard D, Yokoi T, McCleod MJ, Fischer JR, Kim YC, Ballas M, Shi K, Soria JC (2016) A phase III study of durvalumab (MEDI4736) with or without tremelimumab for previously treated patients with advanced NSCLC: rationale and protocol design of the ARCTIC study. Clin Lung Cancer 17:232–236.e1CrossRefPubMedGoogle Scholar