Immunotherapies for NSCLC: Are We Cutting the Gordian Helix?

Chemotherapy is currently the standard-of-care for non-oncogene-driven advanced non-small cell lung cancer (NSCLC). Due to improvements in chemotherapeutic choices and supportive care, patients currently typically undergo multiple lines of chemotherapy as their disease progresses. Although treatments have improved over recent years, limited benefits are seen, especially in patients receiving later-line chemotherapy, as response rates can be low, response duration short and survival poor. Molecular-targeted therapies have provided improvement in outcomes. However, these treatments only offer a clear benefit in subsets of tumors harbouring the appropriate genomic alteration (mutation, amplification, translocation). Recent advances in immunotherapy have highlighted the potential of immuno-oncology-based treatments for NSCLC, offering the potential to provide durable responses and outcomes regardless of histology or mutation status. Blocking inhibitory pathways such as the cytotoxic lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) checkpoint pathways with monoclonal antibodies has generated antitumor immune responses that are transforming cancer therapeutics. PD-1 and programmed cell death ligand-1(PD-L1) antibodies have shown durable responses in NSCLC, with a favourable safety profile and manageable side-effects. The activity of immune checkpoint inhibitors is currently been assessed in treatment-naïve patients with PD-L1-positive advanced NSCLC. Combinatorial approaches with other immune checkpoint inhibitors, chemotherapy, or targeted-agents are being explored in ongoing clinical trials, and may improve outcome in NSCLC. The emerging data not only offer the hope of a better cancer therapy but also provide evidence that changes our understanding on how the host immune system interacts with human cancer. It is therefore conceivable that agents blocking the CTLA-4/PD-1/PD-L1 axis will provide valuable additions to the growing armamentarium of targeted-agents.