title: Immune checkpoint inhibitors in NSCLC.
abstract: Lung cancer is the leading cause of cancer-related mortality worldwide. Cytotoxic chemotherapy and tyrosine kinase inhibitors provide palliation and prolong survival, however, the median survival for patients with metastatic disease remains poor and more effective therapies are needed. Immune checkpoint inhibitors have shown promising results in phase I trials and are being evaluated in ongoing clinical trials in both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) patients. These include agents targeting the programmed cell death-1 receptor and its ligand (PD-1/PD-L1; notably nivolumab, pembrolizumab, MPDL3280A, and MEDI-4736) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4; ipilimumab and tremelimumab); these agents induce antitumor responses by inhibiting critical negative T cell regulators. In particular, the anti-PD-1/PD-L1 therapies administered as single agent therapy in chemotherapy refractory patients have produced objective response rates ranging from 15 %-25 %, the majority of which were rapid and ongoing 1 year after starting therapy. Furthermore, the toxicity profile for these agents differs from that of cytotoxic chemotherapy but generally is much better tolerated. Promising biomarkers, particularly tumor expression of PD-L1 and tumor infiltrating lymphocytes, may aid in treatment selection and stratification. Ongoing evaluation is needed to define the most appropriate timing and patient population that will benefit from therapy with an immune checkpoint inhibitors and the role of combining these agents with existing therapies including systemic therapy and radiation.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, 777 Preston Research Building, Nashville, TN, 37232, USA, douglas.b.johnson@vanderbilt.edu.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Johnson
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Rioth
authors.forename: Leora
authors.initials: L
authors.lastname: Horn
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D056747:Immunomodulation / Q000187:drug effects; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D058990:Molecular Targeted Therapy
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007155:Immunologic Factors
references.citation: J Natl Cancer Inst. 2010 Sep 22;102(18):1388-97
references.pmid: 20826737
references.citation: J Clin Oncol. 2012 Jun 10;30(17):2046-54
references.pmid: 22547592
references.citation: J Clin Oncol. 2005 Dec 10;23(35):8968-77
references.pmid: 16204013
references.citation: N Engl J Med. 2012 Jun 28;366(26):2443-54
references.pmid: 22658127
references.citation: Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8372-7
references.pmid: 12826605
references.citation: Clin Cancer Res. 2009 Dec 1;15(23):7412-20
references.pmid: 19934295
references.citation: Ann Oncol. 2013 Jan;24(1):75-83
references.pmid: 22858559
references.citation: J Clin Oncol. 2008 Jul 20;26(21):3543-51
references.pmid: 18506025
references.citation: J Clin Oncol. 2013 Feb 10;31(5):616-22
references.pmid: 23295794
references.citation: N Engl J Med. 2012 Jun 28;366(26):2455-65
references.pmid: 22658128
references.citation: Cancer Immunol Res. 2013 Jul;1(1):32-42
references.pmid: 24777248
references.citation: Oncologist. 2008;13 Suppl 4:2-9
references.pmid: 19001145
references.citation: J Clin Oncol. 2008 Nov 10;26(32):5275-83
references.pmid: 18838703
references.citation: N Engl J Med. 2002 Jan 10;346(2):92-8
references.pmid: 11784875
references.citation: JAMA. 2004 Jul 28;292(4):470-84
references.pmid: 15280345
references.citation: Lancet Oncol. 2011 Aug;12(8):735-42
references.pmid: 21783417
references.citation: Cancer Immunol Res. 2013 Aug;1(2):85-91
references.pmid: 24777499
references.citation: N Engl J Med. 2013 Jun 20;368(25):2385-94
references.pmid: 23724913
references.citation: N Engl J Med. 2013 Jul 11;369(2):122-33
references.pmid: 23724867
references.citation: Med Oncol. 2011 Sep;28(3):682-8
references.pmid: 20373055
references.citation: CA Cancer J Clin. 2014 Jan-Feb;64(1):9-29
references.pmid: 24399786