Blood Testing to Detect Cancer Recurrence in Patients With Early-Stage Non-Small Cell Lung Cancer

This prospective, single-center observational cohort study will evaluate the clinical validity of a blood-based circulating tumor DNA (ctDNA) assay for detecting molecular residual disease (MRD) and predicting recurrence in patients with surgically resectable stage IB-IIIA non-small cell lung cancer (NSCLC), as defined by the American Joint Committee on Cancer (AJCC) 9th edition. Approximately 200 treatment-naïve adults who are considered surgical candidates by their treating physicians will be enrolled at Fox Chase Cancer Center over approximately two years.

Participants will receive standard-of-care treatment according to multidisciplinary tumor board recommendations and the treating physician's clinical judgment. Treatment pathways may include surgery followed by adjuvant therapy, neoadjuvant chemoimmunotherapy followed by surgery and adjuvant therapy, or neoadjuvant therapy followed by surgery and observation. The protocol does not assign anticancer treatment or specify the selection of therapeutic agents.

Tumor tissue and peripheral blood will be collected for MRD assessment. Tumor tissue will preferably be obtained before neoadjuvant treatment; surgical tissue may be used when a pretreatment specimen is unavailable or when participants proceed directly to surgery. Blood samples for ctDNA analysis will be collected at baseline and at protocol-specified treatment time points. A postoperative blood sample obtained four to six weeks after surgery will establish the landmark MRD assessment. Additional samples will be collected during and after adjuvant treatment, as applicable. During surveillance, MRD blood samples will be collected every three months for the first three years and every six months thereafter, for up to five years.

Clinical disease assessments will use standard-of-care computed tomography (CT) scans, radiology reports, and the treating physician's clinical assessment. Participants will be followed for up to five years after surgery or until radiographically confirmed disease progression, subject to protocol discontinuation criteria. Participants who initiate neoadjuvant therapy but do not undergo surgery will remain in follow-up, with blood collection continuing when feasible. Their available data will contribute to exploratory analyses, but they will not be evaluable for analyses requiring surgical pathology or the postoperative landmark assessment.

The primary objective is to determine the proportion of evaluable participants with documented recurrence in whom ctDNA predicts recurrence at least three months before clinical confirmation. The primary analysis will evaluate recurrence within 36 months after surgery. Secondary objectives include assessing the association between postoperative landmark ctDNA status and recurrence-free survival; determining the proportion of participants with negative ctDNA results at treatment entry; evaluating the sensitivity, specificity, positive predictive value, and negative predictive value of landmark ctDNA results for three-year recurrence; and measuring the interval between the first positive ctDNA result and clinically confirmed recurrence. Recurrence-free survival is defined as the time from the four-to-six-week postoperative ctDNA measurement to the first documented recurrence or death from any cause.

Exploratory analyses will examine longitudinal ctDNA patterns and associations with treatment pathways, clinicopathologic characteristics, genomic alterations, and recurrence. In the first 50 participants receiving neoadjuvant therapy, additional blood, surgical tumor or tumor-bed tissue, lymph node tissue, and stool samples will support correlative studies. These studies will evaluate immune cell profiles, T-cell clonotype dynamics, and gut microbiome characteristics in relation to pathologic response, MRD status, and disease recurrence.