Targeting the Immune System in Non-Small Cell Lung Cancer

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Harnessing the immune system to treat patients with non-small cell lung cancer (NSCLC) represents a novel and exciting new treatment approach, explains Karen L. Reckamp, MD, MS. The most promising agents target the immune checkpoint PD-1 and its ligand, PD-L1. These agents work by inhibiting the tumor's defense mechanism that allows it to suppress antitumor immune activity.

Agents that target immune checkpoints represent a possible shift in the treatment paradigm for patients with NSCLC, believes Roy S. Herbst, MD, PhD. The anti-PD-1 antibody nivolumab demonstrated response rates of up to 20% in patients with NSCLC, explains Herbst. Interestingly, many of these responses come in patients with difficult-to-treat tumors, such as RAS mutated and those refractory to EGFR or ALK targeted therapies. As a result, treatments in this class may be effective in both the refractory and frontline setting.

The median duration of response to PD-1-targeted agents lasts for a substantial period of time, notes Herbst. Furthermore, the response continues following the discontinuation of treatment, suggesting a reprogramming of the immune system to recognize the tumor.

Researchers are exploring possible markers of response for treatment with PD-1 inhibitors, such as PD-L1 expression. However, this investigation is particularly difficult, since PD-L1 expression can be induced by interferon-gamma, Herbst believes. As a result, the effectiveness of this marker is heavily reliant on the quality of the biopsy and tissue collected.

However, research into the PD-L1 inhibitor MPDL3280A seems to indicate that PD-L1 expression correlates to a better response in patients with NSCLC. A phase I study of 85 patients with NSCLC found a response rate of 21% that was enhanced to 46% for patients with PD-L1 expression. In addition to PD-L1, the investigation of other markers will continue to increase as the focus of research shifts toward combination strategies, believes Herbst.