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

2019

Joshua Bauml, MD

Perelman School of Medicine—University of Pennsylvania, Abramson Cancer Center

Philadelphia

The lung cancer treatment landscape is rapidly evolving with the advent of immunotherapy. Now, three checkpoint inhibitors are available in the first-line and second-line settings for certain subsets of patients with advanced-stage NSCLC. Despite this promise, a large subset of patients treated with immunotherapy will not respond to these drugs. This lack of response may be attributed to immune suppressive mechanisms, such as interferon signaling.

Dr. Joshua Bauml’s laboratory is studying pathways that block interferon signaling, such as the JAK-STAT pathway. He proposes to conduct a phase II combination clinical trial (the immunotherapy drug pembrolizumab with the JAK-STAT pathway inhibitor itacitinib) in patients with advanced-stage NSCLC. Dr. Bauml postulates that the combination regimen will remove the immune suppressive effects of interferon signaling and enhance the action of pembrolizumab. He will also be collecting tumor and blood samples during the course of the trial and characterize these samples to identify molecular predictors of response in patients.

Research Summary

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.

Technical Abstract

Immunotherapy has transformed treatment for patients with lung cancer, but most patients still do not respond. Interferon signaling has a dichotomous role—without acute signaling, responses cannot occur, whereas persistent signaling can drive adaptive resistance. Our group recently reported in Cell that delayed administration of a JAK inhibitor in combination with immunotherapy can lead to enhanced treatment responses. We have opened a trial to test this approach, but also aim to improve patient selection and monitoring during immunotherapy by studying key parameters of T-cell exhaustion using peripheral blood flow cytometry. Our group recently showed that one could predict which patients would be most likely to respond to PD-1 blockade in this fashion.

Objective/Hypothesis

We hypothesize that in patients with metastatic non-small cell lung cancer (NSCLC) overexpressing PD-L1 (PD-L1=50%), treatment with pembrolizumab followed by delayed administration of itacitinib will improve the objective response rate. We will also measure the impact of this treatment on key parameters of T cell exhaustion and other biomarkers.

Study Design

This is an optimal three-stage trial of pembrolizumab and itacitinib for first-line treatment of PD-L1=50% metastatic NSCLC. Up to 48 evaluable patients with previously untreated metastatic NSCLC with tumor PD-L1=50% will be enrolled. Beginning with cycle 3 of pembrolizumab, the patient will receive itacitinib for 6 weeks. After 6 weeks of treatment with itacitinib, repeat imaging and tumor biopsy will be performed. Objective response by RECIST 1.1 will be determined based on this scan. Pembrolizumab monotherapy will then be resumed in the absence of progression. Serial blood and tumor samples will be used to monitor established biomarkers and markers of T-cell exhaustion using flow cytometry.

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

Objective/Hypothesis

Study Design

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