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Lung Cancer PD-1 and PD-L1 Inhibitors in Advanced Non-small Cell Lung Cancer— Promising Agents and Evolving Questions Adrian G Sacher, MD 1 and Leena Gandhi, MD, PhD 2 1. Advanced Fellow in Thoracic Oncology; 2. Assistant Professor of Medicine Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute/Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, US Abstract There exists increasing evidence that PD-1 and PD-L1 inhibitors may be effective in the treatment of non-small cell lung cancer (NSCLC)— an unforeseen finding given the early failure of several immuno- and vaccine-based therapies in this field. This suggests that NSCLC is a more immunogenic tumor than initially appreciated and that it may manipulate various immune checkpoints in order to blunt a potential anti-tumor immune response. NSCLC has subsequently been shown to commonly overexpress PD-L1 as a means of suppressing such cell-mediated immune response through PD-1-mediated signaling. Numerous PD-1 and PD-L1 inhibitors are currently in development as well as various combinations of these inhibitors with chemotherapy, kinase inhibitors, and other immune checkpoint inhibitors. Although these treatments have demonstrated clinical activity in early phase clinical trials, reliable data on the impact of these agents on clinically meaningful endpoints in advanced NSCLC remains scarce. Important questions remain unanswered regarding the appropriate use of PD-L1 expression as a predictive biomarker for the use of these agents as well as the ability of the aforementioned drug combinations to achieve durable disease control. Keywords NSCLC, immunotherapy, PD-1, PD-L1 Disclosure: Adrian G Sacher, MD, has received travel fees from AstraZeneca and Genentech/Roche. Leena Gandhi, MD, PhD, has received consultant fees and honoraria from Merck Pharmaceuticals and consultant fees from Genentech/Roche. No funding was received in the publication of this article. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Received: January 15, 2015 Accepted: March 4, 2015 Citation: Oncology & Hematology Review, 2015;11(1):36–42 Correspondence: Leena Gandhi, MD, PhD, Dana-Farber Cancer Institute 450 Brookline Ave, Dana 1234, Boston, Massachusetts, US. E: The use of immunotherapy in advanced non-small cell lung cancer (NSCLC) has long been investigated in advanced NSCLC. The frequent presence of tumor infiltrating lymphocytes (TILs) noted in numerous tumor types provided early evidence of the potential immunogenicity of several cancers including NSCLC. 1,2 However, initial attempts to exploit this therapeutically through tumor vaccines, interleukin (IL)-2, interferon, and similar immunotherapies were generally met with limited success. 3,4 The significant clinical benefit from cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immune checkpoint inhibitors found in melanoma led to clinical trials of ipilimumab attempting to demonstrate similar benefit in NSCLC. 5 Although modest activity was demonstrated with both ipilimumab and certain vaccine-based therapeutic strategies and some clinical trials are still ongoing, 5–11 there has been pessimism in the field regarding the utility of immunotherapy in NSCLC. The development of programmed cell death protein 1 (PD-1) and programmed cell death-ligand protein 1 (PD-L1) inhibitors and their observed clinical activity in advanced NSCLC reinvigorated the study of immunotherapy in this tumor type and suggested NSCLC must utilize 36 powerful mechanisms to evade and dampen the immune response in order to proliferate despite potential immunogenic features. The PD-1/PD-L1 signaling pathway represents a key immune checkpoint that allows NSCLC to evade immune surveillance and whose activation, in concert with other mechanisms, may explain the lacklustre performance of early attempts at immunotherapy. The PD-1/PD-L1 pathway represents a promising therapeutic target under active investigation in NSCLC and a foundation upon which to build multidrug immunotherapy strategies. Immunogenicity and Mechanisms of Immune Escape in NSCLC The tumor stroma consists of a complex infiltrate of various cell types including both inflammatory cells and TILs. 2 The presence of this immune infiltrate provided early evidence of the potential relationship between the immune system and several tumor types including NSCLC. The composition of the immune infiltrate associated with NSCLC exhibits variability between patients. An increased proportion of TILs relative to other inflammatory cells in the tumor stroma have been associated with improved prognosis in both the prospective and retrospective cohorts of patients with advanced Touch ME d ica l ME d ia