Immunotherapy in Non-Small Cell Lung Cancer

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Foundational research into the underlying mechanisms related to tumor-induced immune suppression on infiltrating lymphocytes and immune cells in the tumor microenvironment has led to therapeutic advances, such as PD-1 inhibition, explains Mark A. Socinski, MD. PD-1 is expressed on immune cells and interacts with PD-L1 and PD-L2 on normal cells. Overexpression of PD-L1 causes the downregulation of PD-1 expressing cells, which is a mechanism hijacked by tumors to avoid the immune system.

The development of a way to combat the downregulation of the immune system through the PD-1 pathway makes sense, Socinski notes. Currently, several antibodies are being developed in the non-small cell lung cancer (NSCLC) setting. On March 4, 2015, the FDA approved the PD-1 inhibitor nivolumab as a treatment for patients with advanced squamous NSCLC who have progressed on or after platinum-based chemotherapy.

Both PD-1 and PD-L1 blocking agents induce a consistent response rate ranging from 15% to 25%, Socinski notes. One of the remarkable things about the response seen with PD-1 inhibition is the durability. The new goal for research is to gain a better understand of the toxicities resulting from these agents, which are very different from standard cytotoxic chemotherapies or the TKI class of drugs. These agents can produce immune-related toxicities that need to be understood.

There is a clear role for immunotherapeutics in lung cancer, Socinski states. Several phase I and II trials are looking at combining these immune checkpoint inhibitors, such as the PD-1 compounds with the anti-CTLA4 agents to further enhance responses. PD-1 and CTLA-4 combinations have demonstrated promise as treatments for patients with melanoma, suggesting they will also be effective in NSCLC.