Circulating Tumor DNA Kinetics Predict Progression-Free and Overall Survival in EGFR TKI-Treated Patients with EGFR-Mutant NSCLC (SWOG S1403).

Abstract

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