Minimal Residual Disease Enhances Prognostic Stratification beyond Pathologic Response in Resectable Non–Small Cell Lung Cancer

PURPOSE: Perioperative chemoimmunotherapy is the standard of care for resectable, locally advanced non-small cell lung cancer (NSCLC). Although pathologic complete response (pCR) correlates with excellent survival outcomes, some patients without pCR still exhibit long-term survival. In this study, we evaluate the added value of minimal residual disease (MRD). EXPERIMENTAL DESIGN: MRD was assessed in 60 patients from the NADIM II trial (NCT03838159) using the Guardant Reveal assay. In NADIM II, patients with NSCLC without EGFR or ALK alterations were randomly assigned to receive neoadjuvant nivolumab plus chemotherapy (experimental arm) or chemotherapy alone, followed by surgery. Patients in the experimental arm with R0 resection received adjuvant nivolumab. RESULTS: The MRD detection rate was 9.6%. MRD after surgery or during adjuvant treatment was associated with inferior event-free survival (EFS) and overall survival [OS; hazard ratio (HR): 10.2; 95% confidence interval (CI), 3.7-28.3 and HR: 10.0; 95% CI, 2.0-49.9, respectively]. All patients with MRD-negative plasma samples in at least two time points were alive [HR: not estimable (NE), P < 0.001], with only one relapse (HR: 41.6; 95% CI, 5.0-348.8), corresponding to a patient relapsing with a single brain metastasis. MRD enhanced the prognostic value of pCR for both EFS (P < 0.001) and OS (P = 0.015). Among non-pCR patients, MRD remained a significant prognostic marker (HR: 6.2; 95% CI, 2.2-17.1 and HR: 6.5; 95% CI, 1.3-32.5, for EFS and OS respectively). All non-pCR patients with MRD-negative results in at least two time points were alive (HR: NE, P = 0.025), with one relapse (HR: 19.9; 95% CI, 2.4-165.6), corresponding to the aforementioned case. CONCLUSIONS: MRD may refine prognostic evaluation beyond pCR in resectable NSCLC undergoing perioperative chemoimmunotherapy.