Purpose: Dynamic changes in circulating tumor DNA (ctDNA) decreased risk of progression, compared with those with persistent are under investigation as an early indicator of treatment outcome. ctDNA at Cycle 3 Day 1 [HR, 0.23; 95% confidence interval (CI), Experimental Design: Serial plasma ctDNA (baseline, 8 weeks, 0.12–0.45; P < 0.0001], with a median progression-free survival and at progression) was prospectively incorporated into the SWOG (PFS) of 15.1 (95% CI, 10.6–17.5) months in the group with S1403 clinical trial of afatinib ± cetuximab in tyrosine kinase clearance of ctDNA versus 4.6 (1.7–7.5) months in the group with inhibitor—naïve, EGFR mutation tissue–positive non–small cell persistent ctDNA. Clearance was also associated with a decreased risk lung cancer. of death (HR, 0.44; 95% CI, 0.21–0.90), P ¼ 0.02; median overall Results: EGFR mutations were detected in baseline ctDNA survival (OS): 32.6 (23.5–not estimable) versus 15.6 (4.9–28.3) months. in 77% (82/106) of patients, associated with the presence of brain Conclusions: Plasma clearance of mutant EGFR ctDNA at and/or liver metastases and M1B stage. Complete clearance of EGFR 8 weeks was highly and significantly predictive of PFS and OS, mutations in ctDNA by 8 weeks was associated with a significantly outperforming RECIST response for predicting long-term benefit.