Worldwide, lung cancer remains the leading cause of cancer-related deaths. The vast majority of lung cancers (about 85%) are non–small cell lung cancers (NSCLCs), for which researchers are evaluating immune checkpoint inhibitors (ICIs), which have exhibited antitumor activity against a range of tumor types.1,2

ICIs are designed to disrupt a tumor’s ability to downregulate patients’ T-cell activity in the tumor microenvironment, thereby evading immune attack. Immune checkpoint proteins are frequently likened to immune system “brakes” — and ICI therapy is described as “releasing the brakes.”3

Currently used ICIs have one of several targets: the cytotoxic T-lymphocyte–associated antigen 4 (CTLA- 4) pathway, the programmed death protein 1 (PD-1) cell surface receptor, and the PD-1 ligand (PD-L1) pathway (PD-1/PD-L1). Some ICI agents, like nivolumab and pembrolizumab, target PD-1 directly while others, like atezolizumab, durvalumab, and avelumab, target PD-L1.4,5

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Several of these anti-PD-1/-PD-L1 ICI agents, and anti-CTLA-4 agents like ipilimumab and tremelimumab, are being evaluated in patients with NSCLC, and the US Food and Drug Administration (FDA) has already approved pembrolizumab and nivolumab as second-line treatments for metastatic NSCLC previously treated with platinum-based chemotherapy.5

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Despite sometimes-remarkable clinical responses to ICI therapy and prolonged overall survival (OS) rates compared to cytotoxic chemotherapy among patients with previously treated advanced NSCLC, most patients with lung cancer still do not benefit from ICI therapy.2,6 It is not clear, however, why that is the case.

The FDA expanded its approval of pembrolizumab to the first-line setting after one trial demonstrated superior progression-free survival (PFS) and OS compared with platinum-based chemotherapy among patients whose lung tumors strongly expressed PD-L1.7 Another trial, however, failed to demonstrate improved outcomes with first-line nivolumab in patients with tumors expressing lower PD-L1 levels.8

The reasons for these different outcomes are not yet clear, but may include the use of different biomarker tests and PD-L1 expression cut-off levels.