Phase II study of pembrolizumab and itacitinib (INCB39110) in NSCLC

Immunotherapy with PD-1 inhibitors can lead to very durable responses in metastatic non-small cell lung cancer, which was previously unheard of. Unfortunately, those who benefit constitute a relatively small subset of patients. Combining PD-1 inhibitors with other drugs to amplify response is an appealing strategy, but our understanding of how to do this rationally is quite limited. In addition, biomarker tests to predict who will benefit most from treatment are not very good at predicting responses. Our study aims to address both of these concerns.

Interferon signaling is a critical part of the body’s immune response to tumors, and can make it better or worse. If one thinks about interferon as a component of inflammation, this makes more sense:  if you get sick, you want an inflammatory response to help get rid of the virus or bacteria making you ill. At the same time, if inflammation persists too long, it can hurt your body (as is seen in autoimmune conditions). Our team recently tried to take advantage of this concept in a mouse disease model, and found a way of combining PD-1 blockade with JAK inhibition (which stops interferon signaling), which led to remarkable anti-tumor responses in mice. We are currently running a study evaluating this same combination and dosing schedule in humans with non-small cell lung cancer.

In parallel with these efforts, we are developing a new biomarker to evaluate patients’ response to immunotherapy. Our group has recently found that we can identify a group of T cells that are “exhausted.” T cells are supposed to identify abnormal cells (like cancer) and get rid of them. Exhausted T cells, just like exhausted people, cannot do their job well. When patients receive a PD-1 inhibitor, their T cells can become “reinvigorated.” As one might imagine, if the T cells do not reinvigorate, they cannot kill the cancer cells.