Anti-PD-1/PD-L1 Immunotherapy in Lung Cancer: Update From the ESMO 2016 Congress

Published: Tuesday, Jan 31, 2017

Epidemiology of Lung Cancer

Lung cancer is the leading cause of cancer-related deaths among men and women in the United States, despite being the second most commonly diagnosed cancer.1 Based on Surveillance, Epidemiology, and End Results (SEER) Program data from 2009 to 2013, cancers of the lung and bronchus account for 57.3 new cases of cancer per 100,000 individuals and 46.0 deaths per 100,000 individuals in the United States each year, and the risk of developing some form of lung or bronchus cancer over the course of a lifetime is about 6.5%. Further, in 2016, it was estimated that more than a quarter of all cancer-related deaths (26.5%; 158,000) will be attributed to lung and bronchus cancer.2 Overall, according SEER data, an estimated 224,390 new cases of lung and bronchus cancer will occur in 2016 in the United States, which represents 13.3% of all new cancer diagnoses.2

Lung cancer is divided into 2 major classes: non–small cell lung cancer (NSCLC) and small cell lung cancer. NSCLC is the most common form of lung cancer (83%).1 The estimated 5-year survival rate is 21%.1

Targeted Therapies for Lung Cancer

Molecular targeted therapy is a strategy for cancer treatment that relies on exploiting the pathways and mutations that enable tumors to grow and progress. Prior to its introduction, treatment for locally or advanced-stage NSCLC was limited to chemotherapy or radiotherapy.3 Therefore, the introduction of agents that target mechanisms of tumor cell (TC) immune evasion has led to additional options for patients with NSCLC.4 NSCLC TCs exploit the programmed death-1 (PD-1) pathway to evade immune surveillance and destruction through upregulation of suppressive cell surface immune checkpoint regulators, making inhibitors of this pathway an attractive target in NSCLC cancer therapy.3 Many investigators are turning attention toward the identification of additional molecular biomarkers to predict targeted therapeutic efficacy in patients. Currently, programmed death ligand-1 (PD-L1) expression from NSCLC TCs and tumor-infiltrating lymphocytes has been most explored as a predictor of efficacy of anti–PD-1/PD-L1 immunotherapy treatment in clinical trials.

PD-1/PD-L Pathway

In the development of cancer therapies, NSCLC was not traditionally considered to be an immunotherapy-responsive tumor type; however, major responses are well documented in reaction to blockade of the PD-1/PD-L1 pathway with anti-PD-L1 monoclonal antibodies.5

Immune checkpoint proteins are located on the surfaces of lymphocytes and other immune cells (ICs). These proteins bind specific membrane-bound ligand partners on the surface of neighboring immune effector cells. These ligand-receptor pairs potentially interact in conjunction with antigen presenting cells (APCs) through specific antigen peptide complexes with the T-cell receptor. Checkpoint pathways regulate coregulatory signals that determine if the T cell will be activated for proliferation, cytokine production, and functional activity or will be inactivated. Coregulatory signals are important to the immune response, as the intensity and duration of the response are controlled through this signaling complex. If the immune system is not activated at the appropriate time, normal tissue may be damaged or it may elicit a chronic autoimmune inflammatory response. Checkpoint pathways are attractive targets for therapeutic intervention, as they are important in regulating the physiological immune response to tumor antigens. An inhibitory immune checkpoint that has been targeted in tumor escape is PD-1 and its ligand, PD-L1.3,5

The PD-1 receptor is expressed on the surface of cells involved in the anti-tumor immune response, including activated T cells (such as regulatory T cells), natural killer cells, and B cells. Its high-affinity ligand, PD-L1, is expressed on the surface of APCs, such as dendritic cells and macrophages, as well as TCs. When PD-L1 binds to the PD-1 receptor, the receptor complex activation induces intracellular inhibitory signaling cascades that lead to dysfunctional tumor-infiltrating T cells. These T cells have exhibited poor proliferation and a reduced capacity to produce cytokines.3 As PD-L1 is reported to be overexpressed on TCs in patients with NSCLC, the enhanced interaction with highly expressed PD-1 on attacking tumor-infiltrating T cells, allows cancer cells to inactivate T cells and thus avoid destruction.5

View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Oncology Best Practice™: Choosing Therapies for Patients with EGFR-Mutant Lung Cancers: More Options... More Decisions... Better OutcomesFeb 28, 20182.0
Clinical Vignette Series: 34th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow®Feb 28, 20182.0
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