While most patients with early-stage lung cancer are cured with surgery, 18% of patients with early-stage disease are unable to receive potentially curative treatment because of age or health issues. A recent review showed that 35% of Veteran patients with early-stage lung cancer did not receive surgery. The number of inoperable patients is expected to grow due to our aging general population and the implementation of CT (computed tomography) screening for lung cancer that is designed to detect early-stage disease. This is a problem that is particularly relevant for the Veteran population as their burden of lung cancer is twice as high as non-Veterans and they are more likely to have an earlier stage of disease at diagnosis. This is a frustrating scenario for a cancer stage that could potentially be cured with the right treatment.

Currently, patients with inoperable lung cancer are treated with stereotactic ablative radiotherapy (SAR), which is a precise, highly focused radiation technique. It produces excellent local control and has increased overall survival with minimal side effects as compared to the alternative options of conventional radiation or no therapy. Unfortunately, patients with inoperable disease who have been treated with SAR develop recurrences, including the spread of the tumor to new areas of the body (metastases). The chemotherapy often employed to reduce the risk of metastases is not offered to patients with inoperable disease for fear of side effects. As a result, 30% of such patients will die from metastases within 3 years. Innovative strategies for the treatment of early-stage lung cancer (a Lung Cancer Research Program Area of Emphasis) in inoperable patients are needed to reduce the risk of developing metastatic disease and improve survival.

A new class of drugs called immune checkpoint inhibitors exploits the body's immune system to target and kill tumor cells. The drug used in the proposed trial, MPDL3280A, blocks signals on tumor cells that allow them to evade the immune system. This study will test whether MPDL3280A can be combined with SAR to safely improve outcome. The rationale for this combination is based on the idea that radiation therapy, a well-known mediator of the immune response will partner with the immune checkpoint inhibitor to enhance the body's immune response against tumor cells and promote tumor cell death. Our preliminary data from animal studies strongly support our idea and show that the combination does indeed improve anti-cancer effects.

The proposed clinical trial seeks to provide the first human evidence for combining SAR with an immune checkpoint inhibitor, with the goal of eradicating subclinical metastatic disease and increasing the cure rate for early-stage lung cancer in patients who cannot tolerate surgery. Patients from the University of California Davis medical community, the Northern California Veterans Affairs Health System and David Grant US Air Force Medical Center will be asked to participate. The first objective is to identify the maximum tolerated dose of MPDL3280A that can be given safely with SAR. Twelve to 18 patients will be enrolled in three dose levels in groups of 3-6 patients. Once the maximum tolerated dose is identified, 15 patients will be treated at that dose. Enrolled patients will be treated with a total of six cycles of MPDL3280A plus SAR delivered concurrently with the third cycle. All patients will be evaluated for response and overall toxicity. There are, as with any clinical trial, risks, but because both treatments have modest and non-overlapping toxicities, we believe that the risks will be tolerable and manageable.

The goals of the proposed study are to establish the feasibility and safety of this approach, determine the safe dose of MPDL3280A, and provide preliminary evidence of increased tumor shrinkage, reduced rates of metastases, and an improved cure rate. Remaining cancer tissue and multiple blood samples will be evaluated to determine the immune response to this treatment. We hope to identify markers of response that could ultimately select patients who are most likely to benefit from this therapy.

This study represents an innovative approach to treating patients because these patients may, for the first time, be shown to tolerate and benefit from systemic therapy. In addition, it is the first trial to study SAR plus immune checkpoint inhibitors in any cancer type. Finally, MPDL3280A has only been tested in late-stage lung cancer, never in early-stage lung cancer. If this approach is safe and effective, a definitive randomized trial in SWOG is planned that could lead to a new standard of care for inoperable lung cancer patients in 5-7 years. Similar strategies could also be employed in treating patients with locally advanced and/or metastatic lung cancer and for early-stage cancers of other types that employ SAR.