Surgery

Statement of the Problem: Cancer develops in a sequenced manner. Patches of lung cells gain the ability to multiply faster than their neighboring normal cells by acquiring mutations. These patches of cells are called “premalignant lesions" (PMLs). Some of these lesions may eventually become cancer. Knowledge about how some PMLs may develop into lung cancer is central to developing tools for Cancer Interception—interrupting the cancer development process and blocking progression to advanced metastatic disease. However, we lack effective lung cancer interception approaches due to our incomplete understanding of the earliest molecular events associated with the development of lung cancer, as well as the challenge in developing personalized tools for early detection and prevention.

Proposed Solution: The Dream Team will use a holistic approach to understand the genetics, immunology, radiological (imaging) profile, and treatment response of patients who show evidence of abnormal lung tissue that puts them at high risk to develop lung cancer. The Team has access to unique groups of patient populations (adenocarcinoma—ADC and squamous cell carcinoma—SCC) with signs of lung cancer risk, and has assembled a collection of blood and tissue specimens from these individuals. The main objective of the Team is to understand how lung cancer develops and test methods that will block the development of cancer. Their three-pronged approach to solve this problem will include:

• Creation of a molecular pre-cancer genome atlas (PCGA) of the lung with the goal of identifying which types of precancerous lung tissue require aggressive treatment and which treatments will block the development of these abnormal lesions to invasive lung cancer.
• Development of two diagnostic tools that can be directly applied in the clinic for simple, yet accurate, detection of early lung cancer: 1) the use of nasal swabs, blood tests, and imaging to confirm whether lung abnormalities found on chest imaging are lung cancer or benign lung disease. 2) blood tests that can identify patients at the earliest stages of lung cancer recurrence, thus enabling their timely and effective intervention with therapies such as those that boost the immune system.
• Development of tests to identify which individuals are most likely to benefit from a number of treatment strategies to intercept lung cancer, including emerging immunotherapies.

Statement of the Problem: Currently, low dose CT (LDCT) screening for lung cancer is recommended for high-risk individuals, defined as current or former smokers (quit within the past 15 years) with a 30-or-more pack-year smoking history, 55 to 74 years of age, and with no evidence of lung cancer. However, uptake of LDCT screening has been impeded by high rates of false-positive results, which in turn add significant physical and emotional stress to patients as well as additional healthcare costs. Since LDCT is now commonly available, lung nodules detected in LDCT scans are plentiful, but imprecise guidelines for care make it a challenge to ensure quality follow-up and expedited diagnoses for those with lung cancer. Furthermore, screening is not available for those who don’t meet the screening criteria (younger age or low smoking history) when they are the exact population among whom lung cancer rates are rising.

Proposed Solution: Leveraging expertise of academic research centers (Massachusetts General Hospital, Broad Institute, and Stanford University) and a non-profit managed-care consortium (Kaiser Permanente), the Dream Team will develop a test called the Lung Cancer Interception Assay (LCIA) to complement LDCT screening.

The proposal is novel in that it will develop complex computational algorithms to combine high-sensitivity/high-accuracy blood-based molecular biomarkers with image-based biomarkers to create the  LCIA assay. At the end of the award period, a streamlined product, the LCIA, will be ready to use in population-level definitive trials for the early detection of lung cancer.

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.