Abstract: Until recently, the treatment of patients with advanced non-small-cell lung cancer (NSCLC) whose tumors did not have a targetable genetic alteration was cytotoxic chemotherapy alone. This treatment provided only modest survival benefit. The introduction of immune checkpoint inhibitors targeting programmed cell death 1 protein (PD-1) signaling pathway in the treatment of patients with NSCLC has had significant effect on patient survival. Atezolizumab, nivolumab and pembrolizumab have been shown to be superior to chemotherapy in patients with recurrent NSCLC. Recently, pembrolizumab has been combined with chemotherapy in the front-line setting and has demonstrated an improvement in overall survival in NSCLC patients as compared to chemotherapy alone. In this review we will focus on the clinical trials that led to approval of combination pembrolizumab and chemotherapy as first-line treatment for patients with advanced NSCLC as well as discuss other combinations of immunotherapy and chemotherapy that have also been evaluated.


Keywords: NSCLC, immunotherapy, chemotherapy, clinical trials


INTRODUCTION

It has become increasingly more evident that the host immune system is integral to tumor survival as the ability to avoid host immune destruction as well as promote inflammation are now recognized as “hallmarks” of cancer.1 In the past decade, much research has been undertaken to understand host immunity and tumor interaction and has led to multiple treatments designed to enhance host immunity against tumor cells.2–4 These treatments were largely based on immune checkpoints, which exist to decrease the immune response to protect the host against damaging inflammation and autoimmunity.4–6 These same immune checkpoints are used by cancer cells in order to evade host immune response. Therefore, agents were formulated against these immune checkpoints in order to relieve the inhibition placed on the host immune system thus allowing for immune-mediated destruction of the tumor.

In advanced non-small-cell lung cancer (NSCLC) there are currently three FDA-approved checkpoint inhibitors based on randomized trials that demonstrated survival advantage with these agents in recurrent NSCLC (Figure 1). Nivolumab and pembrolizumab are monoclonal antibodies targeting the programmed death receptor 1 (PD-1) receptor, atezolizumab, a monoclonal antibody, targets programmed death ligand 1 (PD-L1). Furthermore, certain patients with advanced NSCLC treated with checkpoint inhibitors have experienced durable, long-term responses adding to the excitement of these drugs. These results prompted evaluation of these agents in the front-line management of advanced NSCLC. In this review, we will examine the clinical trial data that evaluated the combination of chemotherapy with immune checkpoint inhibitors for the front-line treatment of advanced NSCLC patients.

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