Skip to main content

Advertisement

SpringerLink
Log in

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

  • Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

AE:

Adverse event

ASCO:

American Society of Clinical Oncology

CI:

Confidence intervals

HR:

Hazard ratio

ICI:

Immune checkpoint inhibitor

IHC:

Immunohistochemistry

irAE:

immune-related adverse event

LDH:

Lactate dehydrogenase

LIPI:

Lung Immune Prognostic Index

MMR:

Mismatch-repair

NLR:

Neutrophil to lymphocyte ratio

Non-Sq:

Non-squamous

NSCLC:

Non-small cell lung cancer

ORR:

Overall response rate

PFS:

Progression-free survival

Sq:

Squamous

TMB:

Tumor mutation burden

TME:

Tumor microenvironment

TNF:

Tumor necrosis factor

References

  1. Torre LA, Siegel RL, Jemal A (2016) Lung cancer statistics. Adv Exp Med Biol 893:1–19

    Article  PubMed  Google Scholar 

  2. Novello S, Barlesi F, Califano R et al (2016) Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 27:v1–v27

    Article  CAS  PubMed  Google Scholar 

  3. Carnio S, Novello S, Mele T, Levra MG, Scagliotti GV (2014) Extending survival of stage IV non-small cell lung cancer. Semin Oncol 41:69–92

    Article  CAS  PubMed  Google Scholar 

  4. Melosky B (2014) Treatment algorithms for patients with metastatic non-small cell, non-squamous lung cancer. Front Oncol 4:256

    PubMed  PubMed Central  Google Scholar 

  5. Ohaegbulam KC, Assal A, Lazar-Molnar E, Yao Y, Zang X (2015) Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends Mol Med 21:24–33

    Article  CAS  PubMed  Google Scholar 

  6. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Borghaei H, Paz-Ares L, Horn L et al (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373:1627–1639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Brahmer J, Reckamp KL, Baas P et al (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373:123–135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Garon EB, Rizvi NA, Hui R et al (2015) Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372:2018–2028

    Article  PubMed  Google Scholar 

  10. Fehrenbacher L, Spira A, Ballinger M et al (2016) Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 387:1837–1846

    Article  CAS  PubMed  Google Scholar 

  11. Hellmann MD, Ciuleanu TE, Pluzanski A et al (2018) Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 378:2093–2104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Okamoto T, Maruyama R, Shoji F, Asoh H, Ikeda J, Miyamoto T, Nakamura T, Miyake T, Ichinose Y (2005) Long-term survivors in stage IV non-small cell lung cancer. Lung Cancer 47:85–91

    Article  PubMed  Google Scholar 

  13. Satoh H, Ishikawa H, Ohara G, Kagohashi K, Kurishima K, Ohtsuka M, Hizawa N (2007) Long-term survivors after chemotherapy in advanced non-small cell lung cancer. Anticancer Res 27:4457–4460

    PubMed  Google Scholar 

  14. Dujon C, Azarian R, Petitpretz P (2009) Long-term survivors of advanced non-small-cell lung cancer: characterisation and prognostic factors in a retrospective study. Rev Mal Respir 26:952–960

    Article  CAS  PubMed  Google Scholar 

  15. Giroux Leprieur E, Lavole A, Ruppert AM, Gounant V, Wislez M, Cadranel J, Milleron B (2012) Factors associated with long-term survival of patients with advanced non-small cell lung cancer. Respirology 17:134–142

    Article  PubMed  Google Scholar 

  16. Van Damme V, Govaerts E, Nackaerts K, Dooms C, Wauters I, Vansteenkiste J (2013) Clinical factors predictive of long-term survival in advanced non-small cell lung cancer. Lung Cancer 79:73–76

    Article  PubMed  Google Scholar 

  17. Gettinger S, Horn L, Jackman D et al (2018) Five-year follow-up of nivolumab in previously treated advanced non-small-cell lung cancer: results from the CA209-003 study. J Clin Oncol 36:1675–1684

    Article  CAS  PubMed  Google Scholar 

  18. National Cancer Institute (2017) Cancer Stat facts: lung and bronchus cancer. https://seer.cancer.gov/statfacts/html/lungb.html. Accessed 13 June 2017

  19. Vokes EE, Ready N, Felip E et al (2018) Nivolumab versus docetaxel in previously treated advanced non-small cell lung cancer (CheckMate 017 and CheckMate 057): 3-year update and outcomes in patients with liver metastases. Ann Oncol 29(4):959–965

    Article  CAS  PubMed  Google Scholar 

  20. Crino L, Bidoli P, Delmonte A et al (2016) Italian cohort of nivolumab Expanded Access Programme (EAP): preliminary data from a real-world population. J Clin Oncol 34:3067-

    Article  Google Scholar 

  21. Leighl NB, Hellmann MD, Hui R, Carcereny E, Felip E, Ahn MJ, Eder JP (2017) KEYNOTE-001: 3-year overall survival for patients with advanced NSCLC treated with pembrolizumab. J Clin Oncol 35:abst 9011

    Article  Google Scholar 

  22. Herbst R, Garon E, Kim D-W et al (2017) KEYNOTE-010: durable clinical benefit in patients with previously treated, PD-L1-expressing NSCLC who completed pembrolizumab. J Thorac Oncol 12:S254–S255

    Article  Google Scholar 

  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:S1840

  24. Gadgeel S, Ciardiello F, Rittmeyer A et al (2017) OAK, a randomized Ph III study of atezolizumab vs docetaxel in patients with advanced NSCLC: results from subgroup analyses. J Thorac Oncol 12:S9–S10

    Article  Google Scholar 

  25. Garassino M, Rizvi N, Besse B et al (2017) Atezolizumab as 1L therapy for advanced NSCLC in PD-L1—selected patients: updated ORR, PFS and OS data from the BIRCH study. J Thorac Oncol 12:S251–S252

    Article  Google Scholar 

  26. Garassino MC, Cho BC, Kim JH et al (2018) Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study. Lancet Oncol 19:521–536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rittmeyer A, Barlesi F, Waterkamp D et al (2017) Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389:255–265

    Article  PubMed  Google Scholar 

  28. Abdel-Rahman O (2016) Correlation between PD-L1 expression and outcome of NSCLC patients treated with anti-PD-1/PD-L1 agents: a meta-analysis. Crit Rev Oncol Hematol 101:75–85

    Article  PubMed  Google Scholar 

  29. Aguiar PN Jr, Santoro IL, Tadokoro H, de Lima Lopes G, Filardi BA, Oliveira P, Mountzios G, de Mello RA (2016) The role of PD-L1 expression as a predictive biomarker in advanced non-small-cell lung cancer: a network meta-analysis. Immunotherapy 8:479–488

    Article  CAS  PubMed  Google 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

  31. Mansfield AS, Dong H (2016) Implications of programmed cell death 1 ligand 1 heterogeneity in the selection of patients with non-small cell lung cancer to receive immunotherapy. Clin Pharmacol Ther 100:220–222

    Article  CAS  PubMed  Google Scholar 

  32. Ilie M, Long-Mira E, Bence C et al (2016) Comparative study of the PD-L1 status between surgically resected specimens and matched biopsies of NSCLC patients reveal major discordances: a potential issue for anti-PD-L1 therapeutic strategies. Ann Oncol 27:147–153

    Article  CAS  PubMed  Google Scholar 

  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 27:1953–1958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. McLaughlin J, Han G, Schalper KA et al (2016) Quantitative assessment of the heterogeneity of PD-L1 expression in non-small-cell lung cancer. JAMA Oncol 2:46–54

    Article  PubMed  PubMed Central  Google Scholar 

  35. Teixido C, Karachaliou N, Gonzalez-Cao M, Morales-Espinosa D, Rosell R (2015) Assays for predicting and monitoring responses to lung cancer immunotherapy. Cancer Biol Med 12:87–95

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Kumar R, Collins D, Dolly S, McDonald F, O’Brien MER, Yap TA (2017) Targeting the PD-1/PD-L1 axis in non-small cell lung cancer. Curr Probl Cancer 41:111–124

    Article  PubMed  Google Scholar 

  37. Govindan R, Ding L, Griffith M et al (2012) Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 150:1121–1134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. de Bruin EC, McGranahan N, Mitter R et al (2014) Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science 346:251–256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. McGranahan N, Furness AJ, Rosenthal R et al (2016) Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351:1463–1469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Carbone DP, Reck M, Paz-Ares L et al (2017) First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med 376:2415–2426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gandara DR, Kowanetz M, Mok TSK et al (2017) Blood-based biomarkers for cancer immunotherapy: tumor mutational burden in blood (bTMB) is associated with improved atezolizumab (atezo) efficacy in 2L + NSCLC (POPLAR and OAK). Ann Oncol 28:1295O

    Article  Google 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 e4

    Google Scholar 

  43. Le DT, Uram JN, Wang H et al (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372:2509–2520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rizvi NA, Hellmann MD, Snyder A et al (2015) Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348:124–128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Schrock A, Sharma N, Peled N et al (2017) Updated dataset assessing tumor mutation burden (TMB) as a biomarker for response to PD-1/PD-L1 targeted therapies in lung cancer (LC). J Thorac Oncol 12:S422

    Article  Google Scholar 

  46. Scilla KA, Bentzen SM, Lam VK et al (2017) Neutrophil-lymphocyte ratio is a prognostic marker in patients with locally advanced (Stage IIIA and IIIB) non-small cell lung cancer treated with combined modality therapy. Oncologist 22:737–742

    Article  CAS  PubMed  PubMed Central  Google 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-e

    Article  Google Scholar 

  48. Bagley SJ, Kothari S, Aggarwal C et al (2017) Pretreatment neutrophil-to-lymphocyte ratio as a marker of outcomes in nivolumab-treated patients with advanced non-small-cell lung cancer. Lung Cancer 106:1–7

    Article  PubMed  Google 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

    Article  CAS  PubMed  Google Scholar 

  50. Lee CK, Man J, Lord S, Links M, Gebski V, Mok T, Yang JC (2017) Checkpoint inhibitors in metastatic EGFR-mutated non-small cell lung cancer—a meta-analysis. J Thorac Oncol 12:403–407

    Article  PubMed  Google Scholar 

  51. Ardizzoni A, Bidoli P, Chiari R et al (2017) Nivolumab in advanced non-squamous NSCLC patients with KRAS mutations: results from the italian expanded access program (EAP). J Thorac Oncol 12:S1804

    Article  Google Scholar 

  52. Gettinger S, Choi J, Mani N et al (2017) Predictive value of measuring somatic mutations and tumor infiltrating lymphocytes for PD-1 axis therapy in non-small cell lung cancer (NSCLC). J Thorac Oncol 12:S430–S431

    Article  Google Scholar 

  53. Olugbile S, Bao R, Hensing T, Nakamura Y, Vokes E (2017) Molecular determinants of lack of tumor immune infiltration in NSCLC. J Thorac Oncol 12:S431–S432

    Article  Google Scholar 

  54. Tumeh PC, Harview CL, Yearley JH et al (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568–571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sanmamed MF, Perez-Gracia JL, Schalper KA et al (2017) Changes in serum interleukin-8 (IL-8) levels reflect and predict response to anti-PD-1 treatment in melanoma and non-small cell lung cancer patients. Ann Oncol 28:1988–1995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Blank CU, Haanen JB, Ribas A, Schumacher TN (2016) Cancer Immunology. The “cancer immunogram”. Science 352:658–660

    Article  CAS  PubMed  Google Scholar 

  57. Mezquita L, Auclin E, Ferrara R et al (2018) Association of the lung immune prognostic index with immune checkpoint inhibitor outcomes in patients with advanced non-small cell lung cancer. JAMA Oncol 4:351–357

    Article  PubMed  PubMed Central  Google Scholar 

  58. Park W, Kwon D, Saravia D et al (2018) Developing a predictive model for clinical outcomes of advanced non-small cell lung cancer patients treated with nivolumab. Clin Lung Cancer 19:280–288 e4

    Article  CAS  PubMed  Google 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 8:8910–8920

    PubMed  Google Scholar 

  60. Cousin S, Italiano A (2016) Molecular pathways: immune checkpoint antibodies and their toxicities. Clin Cancer Res 22:4550–4555

    Article  CAS  PubMed  Google 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 33:3193–3198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Weber JS, Hodi FS, Wolchok JD et al (2017) Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol 35:785–792

    Article  CAS  PubMed  Google 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:S233

    Google Scholar 

  64. Martínez Bernal G, Mezquita L, Auclin E et al (2017) Baseline corticosteroids (CS) could be associated with absence of benefit to immune checkpoint inhibitors (ICI) in advanced non-small cell lung cancer (NSCLC) patients. Ann Oncol 28:1323

    Article  Google Scholar 

  65. Zhang T, Xie J, Arai S et al (2016) The efficacy and safety of anti-PD-1/PD-L1 antibodies for treatment of advanced or refractory cancers: a meta-analysis. Oncotarget 7:73068–73079

    PubMed  PubMed Central  Google Scholar 

  66. Pillai R, Behera M, Owonikoko T, Kamphorst A, Pakkala S, Belani C, Khuri F, Ahmed R, Ramalingam S (2017) Evaluation of toxicity profile of PD-1 versus PD-L1 inhibitors in non-small cell lung cancer (NSCLC). J Thorac Oncol 12:S253–S254

    Article  Google Scholar 

  67. Downey SG, Klapper JA, Smith FO et al (2007) Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res 13:6681–6688

    Article  CAS  PubMed  PubMed Central  Google 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, Austria

  69. Hua C, Boussemart L, Mateus C et al (2016) Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol 152:45–51

    Article  PubMed  Google Scholar 

  70. Sanlorenzo M, Vujic I, Daud A et al (2015) Pembrolizumab cutaneous adverse events and their association with disease progression. JAMA Dermatol 151:1206–1212

    Article  PubMed  PubMed Central  Google Scholar 

  71. Osorio JC, Ni A, Chaft JE et al (2017) Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. Ann Oncol 28:583–589

    CAS  PubMed  Google 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 28:1314P

    Google 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 Oncol

  74. Melero I, Berman DM, Aznar MA, Korman AJ, Perez Gracia JL, Haanen J (2015) Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer 15:457–472

    Article  CAS  PubMed  Google Scholar 

  75. Marshall R, Popple A, Kordbacheh T, Honeychurch J, Faivre-Finn C, Illidge T (2017) Immune checkpoint inhibitors in lung cancer—an unheralded opportunity? Clin Oncol (R Coll Radiol) 29:207–217

    Article  CAS  Google 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 18:333–339

    Article  CAS  PubMed  Google Scholar 

  77. Zitvogel L, Kepp O, Kroemer G (2011) Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat Rev Clin Oncol 8:151–160

    Article  CAS  PubMed  Google Scholar 

  78. Rizvi NA, Hellmann MD, Brahmer JR et al (2016) Nivolumab in combination with platinum-based doublet chemotherapy for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol 34:2969–2979

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Juergens R, Hellmann M, Brahmer J et al (2017) First-line nivolumab plus platinum-based doublet chemotherapy for advanced NSCLC: checkmate 012 3-year update. J Thorac Oncol 12:S1792–S1793

    Article  Google Scholar 

  80. Langer CJ, Gadgeel SM, Borghaei H et al (2016) Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 17:1497–1508

    Article  CAS  PubMed  PubMed Central  Google 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:LBA49

    Google Scholar 

  82. Gandhi L, Rodriguez-Abreu D, Gadgeel S et al (2018) Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 378:2078–2092

    Article  CAS  PubMed  Google Scholar 

  83. Paz-Ares LG, Luft A, Tafreshi A et al (2018) Phase 3 study of carboplatin-paclitaxel/nab-paclitaxel (Chemo) with or without pembrolizumab (Pembro) for patients (Pts) with metastatic squamous (Sq) nonsmall cell lung cancer (NSCLC). American Society of Clinical Oncology, Chicago

    Book  Google Scholar 

  84. Liu SV, Powderly JD, Camidge DR et al (2015) Safety and efficacy of MPDL3280A (anti-PDL1) in combination with platinum-based doublet chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol 33:8030-

    Article  Google Scholar 

  85. Larkin J, Chiarion-Sileni V, Gonzalez R et al (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373:23–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Hellmann MD, Rizvi NA, Goldman JW et al (2017) Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol 18:31–41

    Article  CAS  PubMed  Google Scholar 

  87. Goldman JW, Antonia S, Gettinger S et al (2017) Nivolumab plus ipilimumab as first-line treatment for advanced NSCLC: 2-year overall survival and long-term outcomes from checkmate 012. J Clin Oncol 35:Abstr 9093

    Article  Google Scholar 

  88. Gubens MA, Sequist LV, Stevenson J et al (2016) Phase I/II study of pembrolizumab (pembro) plus ipilimumab (ipi) as second-line therapy for NSCLC: KEYNOTE-021 cohorts D and H. J Clin Oncol 34:9027-

    Article  Google Scholar 

  89. Antonia S, Goldberg SB, Balmanoukian A et al (2016) Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol 17:299–308

    Article  CAS  PubMed  PubMed Central  Google 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.e1

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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.

Funding

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.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Catalan Institute of Oncology (ICO), Avda Gran via, 199-203. L’Hospitalet, 08908, Barcelona, Spain

    Ernest Nadal

  2. Clinical Research in Solid Tumors (CReST) Group, OncoBell Program, IDIBELL, L’Hospitalet, Barcelona, Spain

    Ernest Nadal

  3. Department of Medical Oncology, Hospital Universitario de Alicante, ISABIAL, Alicante, Spain

    Bartomeu Massuti

  4. Department of Medical Oncology, Hospital Universitario Fundación Jiménez Díaz, Oncohealth Institute, Universidad Autónoma de Madrid, Madrid, Spain

    Manuel Dómine

  5. Department of Medical Oncology, A Coruña University Hospital, A Coruña, Spain

    Rosario García-Campelo

  6. Medical Oncology Department, Hospital Universitario Málaga Regional y Virgen de la Victoria, IBIMA, Málaga, Spain

    Manuel Cobo

  7. Lung Cancer Unit, Hospital Universitari Vall d’Hebron and Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain

    Enriqueta Felip

Authors
  1. Ernest Nadal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bartomeu Massuti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Manuel Dómine
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rosario García-Campelo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Manuel Cobo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Enriqueta Felip
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding author

Correspondence to Ernest Nadal.

Ethics declarations

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.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nadal, E., Massuti, B., Dómine, M. et al. Immunotherapy with checkpoint inhibitors in non-small cell lung cancer: insights from long-term survivors. Cancer Immunol Immunother 68, 341–352 (2019). https://doi.org/10.1007/s00262-019-02310-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-019-02310-2

Keywords

Search

Navigation