• Barbara Melosky, Quincy Chu, Rosalyn Juergens, Natasha Leighl, Deanna McLeod, and Vera Hirsh.
• 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.
• J. Clin. Oncol. 2016 May 10; 34 (14): 1676-88.

PurposeNon-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.MethodsOur 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.ResultsA 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.ConclusionLevel 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.© 2016 by American Society of Clinical Oncology.

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