Download PDF
Semin Respir Crit Care Med 2020; 41(03): 400-408
DOI: 10.1055/s-0040-1710077
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Immunotherapy in Advanced Non-Small Cell Lung Cancer

Joy Huang
1   Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California
,
Karen L. Reckamp
1   Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California
› Author Affiliations
Further Information

Publication History

Publication Date:
25 May 2020 (online)

    Permissions and Reprints

Abstract

Traditionally, lung cancer has been treated as an immune-resistant disease with platinum-based chemotherapy serving as the first-line treatment for metastatic disease. The efficacy of immunotherapy has been established for patients with advanced lung cancer in clinical trials, and it has since become the standard of care for patients without targetable mutations, with or without chemotherapy. Previously, lung cancer patients experienced limited responses to immune-based therapy. As clinical trials continued to explore immunotherapy options with checkpoint inhibitors, results showed that immune therapies can create durable responses with manageable toxicities. Patients with advanced non-small cell lung cancer (NSCLC) can experience improved survival when administered immunotherapy over chemotherapy. The first successful immunotherapy treatments developed exploit programmed death 1/programmed death ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), immune checkpoint pathways. Combination therapies of PD-1/PD-L1 inhibitors and chemotherapy or PD-1/PD-L1 and CTLA-4 checkpoint pathway inhibitors have also demonstrated improved outcomes for patients with NSCLC. Combination therapy with PD-1 or PD-L1 therapy and chemotherapy has shown benefit for small cell lung cancer patients as well. As immunotherapy changes the treatment paradigm of lung cancer, researchers continue to investigate different combinations, timing, duration, and biomarkers to better understand and improve the efficacy of immune-based therapy for patients with lung cancer.

Keywords

non-small cell lung cancer - immunotherapy - PD-1 - PDL-1 - CTLA-4
 

  • References

  • 1 Schultz KT, Grieder F. Structure and function of the immune system. Toxicol Pathol 1987; 15 (03) 262-264
    CrossrefPubMedGoogle Scholar
  • 2 Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Ann Oncol 2012; 23 (Suppl. 08) viii6-9
    PubMedGoogle Scholar
  • 3 Carbone DP, Gandara DR, Antonia SJ, Zielinski C, Paz-Ares L. Non-small-cell lung cancer: role of the immune system and potential for immunotherapy. J Thorac Oncol 2015; 10 (07) 974-984
    CrossrefPubMedGoogle Scholar
  • 4 Medzhitov R, Janeway Jr CA. Innate immune recognition and control of adaptive immune responses. Semin Immunol 1998; 10 (05) 351-353
    CrossrefPubMedGoogle Scholar
  • 5 Mittal D, Gubin MM, Schreiber RD, Smyth MJ. New insights into cancer immunoediting and its three component phases--elimination, equilibrium and escape. Curr Opin Immunol 2014; 27: 16-25
    CrossrefPubMedGoogle Scholar
  • 6 Brahmer JR, Pardoll DM. Immune checkpoint inhibitors: making immunotherapy a reality for the treatment of lung cancer. Cancer Immunol Res 2013; 1 (02) 85-91
    CrossrefPubMedGoogle Scholar
  • 7 Reck M, Heigener DF, Mok T, Soria JC, Rabe KF. Management of non-small-cell lung cancer: recent developments. Lancet 2013; 382 (9893): 709-719
    CrossrefPubMedGoogle Scholar
  • 8 Brahmer JR. Immune checkpoint blockade: the hope for immunotherapy as a treatment of lung cancer?. Semin Oncol 2014; 41 (01) 126-132
    CrossrefPubMedGoogle Scholar
  • 9 Sharpe AH, Pauken KE. The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol 2018; 18 (03) 153-167
    CrossrefPubMedGoogle Scholar
  • 10 Sundar R, Cho BC, Brahmer JR, Soo RA. Nivolumab in NSCLC: latest evidence and clinical potential. Ther Adv Med Oncol 2015; 7 (02) 85-96
    CrossrefPubMedGoogle Scholar
  • 11 Robainas M, Otano R, Bueno S, Ait-Oudhia S. Understanding the role of PD-L1/PD1 pathway blockade and autophagy in cancer therapy. OncoTargets Ther 2017; 10: 1803-1807
    CrossrefPubMedGoogle Scholar
  • 12 Lesokhin AM, Callahan MK, Postow MA, Wolchok JD. On being less tolerant: enhanced cancer immunosurveillance enabled by targeting checkpoints and agonists of T cell activation. Sci Transl Med 2015; 7 (280) 280sr1
    CrossrefPubMedGoogle Scholar
  • 13 Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 2017; 168 (04) 707-723
    CrossrefPubMedGoogle Scholar
  • 14 Garon EB, Rizvi NA, Hui R. , et al; KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015; 372 (21) 2018-2028
    CrossrefPubMedGoogle Scholar
  • 15 Garon EB, Hellmann MD, Rizvi NA. , et al. Five-year overall survival for patients with advanced non-small-cell lung cancer treated with pembrolizumab: results from the phase I KEYNOTE-001 study. J Clin Oncol 2019; 37 (28) 2518-2527
    CrossrefPubMedGoogle Scholar
  • 16 Reck M, Rodríguez-Abreu D, Robinson AG. , et al; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016; 375 (19) 1823-1833
    CrossrefPubMedGoogle Scholar
  • 17 Mok TSK, Wu Y-L, Kudaba I. , et al; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 2019; 393 (10183): 1819-1830
    CrossrefPubMedGoogle Scholar
  • 18 Carbone DP, Reck M, Paz-Ares L. , et al; CheckMate 026 Investigators. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med 2017; 376 (25) 2415-2426
    CrossrefPubMedGoogle Scholar
  • 19 Rizvi NA, Hellmann MD, Snyder A. , et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015; 348 (6230): 124-128
    CrossrefPubMedGoogle Scholar
  • 20 Gandhi L, Rodríguez-Abreu D, Gadgeel S. , et al; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 2018; 378 (22) 2078-2092
    CrossrefPubMedGoogle Scholar
  • 21 Paz-Ares L, Luft A, Vicente D. , et al; KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med 2018; 379 (21) 2040-2051
    CrossrefPubMedGoogle Scholar
  • 22 Socinski MA, Jotte RM, Cappuzzo F. , et al; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 2018; 378 (24) 2288-2301
    CrossrefPubMedGoogle Scholar
  • 23 Lynch TJ, Bondarenko I, Luft A. , et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol 2012; 30 (17) 2046-2054
    CrossrefPubMedGoogle Scholar
  • 24 Govindan R, Szczesna A, Ahn MJ. , et al. Phase III trial of ipilimumab combined with paclitaxel and carboplatin in advanced squamous non-small-cell lung cancer. J Clin Oncol 2017; 35 (30) 3449-3457
    CrossrefPubMedGoogle Scholar
  • 25 Hellmann MD, Ciuleanu TE, Pluzanski A. , et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 2018; 378 (22) 2093-2104
    CrossrefPubMedGoogle Scholar
  • 26 Ready N, Hellmann MD, Awad MM. , et al. First-line nivolumab plus ipilimumab in advanced non-small-cell lung cancer (CheckMate 568): outcomes by programmed death ligand 1 and tumor mutational burden as biomarkers. J Clin Oncol 2019; 37 (12) 992-1000
    CrossrefPubMedGoogle Scholar
  • 27 Herbst RS, Baas P, Kim DW. , et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016; 387 (10027): 1540-1550
    CrossrefPubMedGoogle Scholar
  • 28 Brahmer J, Reckamp KL, Baas P. , et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015; 373 (02) 123-135
    CrossrefPubMedGoogle Scholar
  • 29 Horn L, Spigel DR, Vokes EE. , et al. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (CheckMate 017 and CheckMate 057). J Clin Oncol 2017; 35 (35) 3924-3933
    CrossrefPubMedGoogle Scholar
  • 30 Borghaei H, Paz-Ares L, Horn L. , et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015; 373 (17) 1627-1639
    CrossrefPubMedGoogle Scholar
  • 31 Fehrenbacher L, Spira A, Ballinger M. , et al; POPLAR Study Group. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 2016; 387 (10030): 1837-1846
    CrossrefPubMedGoogle Scholar
  • 32 Bordoni R, Ciardiello F, von Pawel J. , et al. Patient-reported outcomes in OAK: a phase III study of atezolizumab versus docetaxel in advanced non-small-cell lung cancer. Clin Lung Cancer 2018; 19 (05) 441-449.e4
    CrossrefPubMedGoogle Scholar
  • 33 Antonia SJ, Villegas A, Daniel D. , et al; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 2017; 377 (20) 1919-1929
    CrossrefPubMedGoogle Scholar
  • 34 Antonia SJ, Villegas A, Daniel D. , et al; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 2018; 379 (24) 2342-2350
    CrossrefPubMedGoogle Scholar
  • 35 Gandara DR, Paul SM, Kowanetz M. , et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med 2018; 24 (09) 1441-1448
    CrossrefPubMedGoogle Scholar
  • 36 Jamal-Hanjani M, Wilson GA, McGranahan N. , et al; TRACERx Consortium. Tracking the evolution of non-small-cell lung cancer. N Engl J Med 2017; 376 (22) 2109-2121
    CrossrefPubMedGoogle Scholar
  • 37 Michot JM, Bigenwald C, Champiat S. , et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 2016; 54: 139-148
    CrossrefPubMedGoogle Scholar
  • 38 Ricciuti B, Genova C, De Giglio A. , et al. Impact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with nivolumab: long-term outcomes from a multi-institutional analysis. J Cancer Res Clin Oncol 2019; 145 (02) 479-485
    CrossrefPubMedGoogle Scholar
  • 39 González-Cao M. Immunotherapy for lung cancer. Transl Lung Cancer Res 2015; 4 (06) 675-677
    PubMedGoogle Scholar