Background: The current standard of care for patients with inoperable stage III non-small cell lung cancer (NSCLC) includes chemoradiation (CRT) followed by up to 1 year of checkpoint inhibitor (CPI) therapy. However, many patients are not able to complete 1 year of treatment and the optimal duration of consolidation therapy remains unknown. Identifying minimal residual disease (MRD) via detection of circulating tumor DNA (ctDNA) may help inform the optimal duration of treatment. Here we report the results of a preplanned correlative study evaluating the association between detectable ctDNA and survival outcomes from the BTCRC LUN 16-081 phase 2 trial of consolidation nivolumab or nivolumab plus ipilimumab following CRT in patients with unresectable Stage III NSCLC (NCT03285321). Methods: Following CRT, patients with unresectable stage IIIA/B NSCLC were randomized 1:1 to receive nivolumab 480 mg IV Q4weeks for up to 6 cycles or nivolumab 240 mg IV Q2weeks plus ipilimumab 1 mg/kg IV Q6weeks for up to 4 cycles. Plasma samples for ctDNA analysis were collected after completion of CRT, prior to C2D1 of CPI, and at the end of treatment or withdrawal from the study. Tumor genotyping and ctDNA analysis were performed using CAPP-Seq with a panel targeting 260 genes recurrently mutated in NSCLC. Patient-specific tumor variants were identified using tumor tissue or baseline plasma and matched leukocyte DNA samples. Tumor variants were then monitored in plasma samples using a tumor mutation-informed bioinformatic strategy. Results: Thirty-nine patients received either nivolumab (n = 25; cycles: median = 6, range 1-6), or nivolumab plus ipilimumab (n = 14; cycles; median = 2, range = 1-6). Patients with detectable ctDNA MRD after completion of CRT demonstrated significantly inferior progression free survival (PFS) than patients who were MRD-negative (12-month 29% vs 76%, 24-month 29% vs 68%, P = 0.003), prior to C2D1 of CPI (12-month 0% vs 85%, 24-month 0% vs 72%, P < 0.0001) and at the end of CPI (12-month 14% vs 90%, 24-month 14% vs 79%, P < 0.0001). Patients with undetectable ctDNA MRD at the end of CPI (median cycles = 5.5; range 1-6) demonstrated 24-month overall survival of 91%. Additionally, patients with decreasing or undetectable ctDNA levels after one cycle of CPI had improved outcomes compared to patients with increasing ctDNA levels (24-month PFS 73% vs 0%, P < 0.0001). Progression of disease occurred within 10.8 months of starting CPI in all patients with increasing ctDNA levels at C2D1. Conclusions: Detectable ctDNA before, during, and after consolidation CPI is strongly associated with inferior survival outcomes. Furthermore, less than 12 months of CPI consolidation can result in MRD negativity and high rates of long term PFS. Clinical trial information: NCT03285321.