Stage II

Evaluating suspicious pulmonary nodules in the setting of a lung cancer diagnostic work-up is a common clinical management challenge. High resolution multi-detector computed tomography visualizes many noncalcified lesions that could represent either potentially lethal cancers or benign processes. Although the vast majority of these nodules are benign, non-neoplastic lesions, a subset will be malignant and in these cases, patients could benefit from immediate treatment. A non-invasive test that maintains a high sensitivity and specificity across the spectrum of clinical presentations of pulmonary nodules would be of tremendous clinical benefit by reducing the number unnecessary invasive procedures and minimizing the time between detection and definitive treatment. The overall goal for the proposed studies is to develop a convenient and low-cost serum test that will, either alone or in combination with clinical features, accurately classify indeterminate nodules and direct proper clinical management. Our approach to develop such a test will be to profile and identify which proteins detected in the serum at the time of the detection of these nodules were immunogenic and induced the production of circulating autoantibodies. Differences in the autoantibody profile between the malignant and non-malignant groups will then be further evaluated against additional clinical specimens from both our institution and two pre-specified collaborator institutions to identify the optimal test for this urgent clinical need. Once completed, we anticipate this test will aid clinicians in deciding the optimal treatment for patients found to have suspicious nodules and improve the current standard of care.

Background & Significance: Phase I studies with the anti-programmed death-1 antibody (anti-PD-1), nivolumab, in advanced non-small-cell lung cancer (NSCLC) have demonstrated remarkably durable responses in heavily pretreated patients that lasted a median 17 months. However, in these studies very few patients have had tumors available for immune analysis, and basic data on immune measures pre- and post-treatment are not available. This study will move the treatment paradigm forward by assessing the safety and feasibility of preoperative anti-PD-1 in NSCLC and providing detailed information on the effect of PD-1 modulation on the lung tumor immune microenvironment.

Methods: Patients with newly diagnosed stage IB-IIIA NSCLC will receive two doses of nivolumab 3mg/kg IV on day-28 and day-14 prior to planned surgery on day 0. Serial blood samples for immune markers will be obtained. The primary endpoint of this study is the safety and feasibility of preoperative nivolumab in resectable NSCLC. For the exploratory immune analyses, initial tumor biopsy, post-treatment resection specimen, and serial peripheral blood samples will be evaluated for expression of immune markers with the primary comparison being intra-patient, pre- and post-treatment.

Experimental Approach & Statistical Analysis Plan: As this is the first time that nivolumab has been administered pre-operatively in NSCLC, the study will commence with a run-in phase where six patients will be monitored continuously for adverse events through eight weeks following surgery. Overall, the study will continue without pause to a 12-patient expansion phase if none or one of the six patients experiences DLT in the run-in. Detailed statistical plans for the safety and feasibility endpoints and exploratory immune endpoints are described in the main body of this application.

Screening smokers with CT can detect lung cancer at relatively early stages, and thus reduce mortality. However, CT screening for lung cancer has a poor specificity, often resulting in unnecessary treatments to smokers who have benign diseases. The objective of this proposal is to develop genomic- and non-coding RNA (ncRNA)-based biomarkers in sputum that can complement CT for lung cancer early detection in smokers.  Proposed aim 1 is to define sputum ncRNA signatures of early-stage lung cancer using next-generation sequencing (NGS). Proposed aim 2 is to optimize a panel of sputum ncRNA biomarkers with CT for the early detection of lung cancer. Proposed aim 3 is to integrate our previously identified genomic biomarkers and the newly optimized panel of ncRNA biomarkers with CT for the early detection of lung cancer in independent case-control series. Future use of the biomarkers in clinical practice for screening smokers for lung cancer will increase CT’s specificity, and hence reduce harmful and unnecessary treatments to many smokers who have benign diseases. Integrating the biomarkers with CT could assist making decisions for the management of abnormal findings in the lungs and enabling effective treatments to be immediately initiated for lung cancer. The study will translate the strengths of novel ncRNA profiling data developed from NGS into clinical settings by using a simple and cost-effective approach, and thus bridge the gap between basic research and patient care.