title: Pointed Progress in Second-Line Advanced Non-Small-Cell Lung Cancer: The Rapidly Evolving Field of Checkpoint Inhibition.
abstract: Non-small-cell lung cancer (NSCLC) is globally prevalent and associated with high rates of mortality. Immune checkpoint pathways are often exploited by tumors to evade immunity-mediated destruction, and checkpoint inhibitors can reactivate tumor-related immune responses. This review considers available clinical evidence for the use of checkpoint inhibitors in the treatment of second-line advanced NSCLC.
  
  
  
  Our systematic search revealed 20 clinical trials evaluating checkpoint inhibitors in the second-line setting, three of which were randomized trials comparing programmed cell death protein 1 and programmed death ligand 1 (PD-L1) inhibitors to docetaxel, the current standard of care in this setting.
  
  
  
  A randomized phase II trial comparing the PD-L1 inhibitor atezolizumab to docetaxel did not demonstrate improved survival for atezolizumab in patients overall, although a trend toward improved survival with increased PD-L1 expression was apparent. Twin phase III trials showed significantly improved survival for the programmed cell death protein 1 inhibitor nivolumab compared with docetaxel in patients with both squamous and nonsquamous disease. PD-L1 expression correlated with improved survival in patients with nonsquamous disease, and patients with low levels of PD-L1 expression (< 10%) and those with EGFR mutations are unlikely to benefit. Checkpoint inhibitor therapy is generally well tolerated and associated with low rates of grade 3 or 4 adverse events compared with standard care.
  
  
  
  Level 1 evidence exists to support the use of nivolumab as second-line treatment of patients with squamous advanced NSCLC, as well as in select patients with nonsquamous disease. Benefits remain unknown in patients with targetable driver mutations, and use of PD-L1 expression to guide therapy remains controversial. Results from ongoing randomized trials evaluating biomarkers and other checkpoint inhibitors will further our understanding of this rapidly evolving area of oncology.
authors.affiliation: Barbara Melosky, British Columbia Cancer Agency, Vancouver Centre, Vancouver, British Columbia; Quincy Chu, Cross Cancer Institute and University of Alberta, Edmonton, Alberta; Rosalyn Juergens, McMaster University, Juravinski Cancer Centre, Hamilton; Natasha Leighl, Princess Margaret Hospital and University of Toronto; Deanna McLeod, Kaleidoscope Strategic, Toronto, Ontario; and Vera Hirsh, Montreal General Hospital, Royal Victoria Hospital, and McGill University, Montreal, Quebec, Canada. bmelosky@bccancer.bc.ca.
authors.forename: Barbara
authors.initials: B
authors.lastname: Melosky
authors.affiliation: Barbara Melosky, British Columbia Cancer Agency, Vancouver Centre, Vancouver, British Columbia; Quincy Chu, Cross Cancer Institute and University of Alberta, Edmonton, Alberta; Rosalyn Juergens, McMaster University, Juravinski Cancer Centre, Hamilton; Natasha Leighl, Princess Margaret Hospital and University of Toronto; Deanna McLeod, Kaleidoscope Strategic, Toronto, Ontario; and Vera Hirsh, Montreal General Hospital, Royal Victoria Hospital, and McGill University, Montreal, Quebec, Canada.
authors.forename: Quincy
authors.initials: Q
authors.lastname: Chu
authors.affiliation: Barbara Melosky, British Columbia Cancer Agency, Vancouver Centre, Vancouver, British Columbia; Quincy Chu, Cross Cancer Institute and University of Alberta, Edmonton, Alberta; Rosalyn Juergens, McMaster University, Juravinski Cancer Centre, Hamilton; Natasha Leighl, Princess Margaret Hospital and University of Toronto; Deanna McLeod, Kaleidoscope Strategic, Toronto, Ontario; and Vera Hirsh, Montreal General Hospital, Royal Victoria Hospital, and McGill University, Montreal, Quebec, Canada.
authors.forename: Rosalyn
authors.initials: R
authors.lastname: Juergens
authors.affiliation: Barbara Melosky, British Columbia Cancer Agency, Vancouver Centre, Vancouver, British Columbia; Quincy Chu, Cross Cancer Institute and University of Alberta, Edmonton, Alberta; Rosalyn Juergens, McMaster University, Juravinski Cancer Centre, Hamilton; Natasha Leighl, Princess Margaret Hospital and University of Toronto; Deanna McLeod, Kaleidoscope Strategic, Toronto, Ontario; and Vera Hirsh, Montreal General Hospital, Royal Victoria Hospital, and McGill University, Montreal, Quebec, Canada.
authors.forename: Natasha
authors.initials: N
authors.lastname: Leighl
authors.affiliation: Barbara Melosky, British Columbia Cancer Agency, Vancouver Centre, Vancouver, British Columbia; Quincy Chu, Cross Cancer Institute and University of Alberta, Edmonton, Alberta; Rosalyn Juergens, McMaster University, Juravinski Cancer Centre, Hamilton; Natasha Leighl, Princess Margaret Hospital and University of Toronto; Deanna McLeod, Kaleidoscope Strategic, Toronto, Ontario; and Vera Hirsh, Montreal General Hospital, Royal Victoria Hospital, and McGill University, Montreal, Quebec, Canada.
authors.forename: Deanna
authors.initials: D
authors.lastname: McLeod
authors.affiliation: Barbara Melosky, British Columbia Cancer Agency, Vancouver Centre, Vancouver, British Columbia; Quincy Chu, Cross Cancer Institute and University of Alberta, Edmonton, Alberta; Rosalyn Juergens, McMaster University, Juravinski Cancer Centre, Hamilton; Natasha Leighl, Princess Margaret Hospital and University of Toronto; Deanna McLeod, Kaleidoscope Strategic, Toronto, Ontario; and Vera Hirsh, Montreal General Hospital, Royal Victoria Hospital, and McGill University, Montreal, Quebec, Canada.
authors.forename: Vera
authors.initials: V
authors.lastname: Hirsh
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000276:immunology*; D017326:Clinical Trials, Phase III as Topic; D000077143:Docetaxel; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D000077594:Nivolumab; D016032:Randomized Controlled Trials as Topic; D043823:Taxoids / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D043823:Taxoids; D000077143:Docetaxel; D000077594:Nivolumab; C000594389:atezolizumab