Serial circulating tumour DNA monitoring in first-line advanced NSCLC (COPE): a randomized, two-arm non-comparative phase II trial

Purpose: COPE evaluated serial circulating tumor DNA (ctDNA) profiling with molecular tumor board (MTB) review during first-line therapy for advanced non–small cell lung cancer (NSCLC). Experimental Design: COPE was a multicenter, randomized (2:1), noncomparative phase II trial. Arm A underwent serial plasma profiling with every report reviewed at a weekly virtual MTB; Arm B received standard management. The primary endpoint was 18-month overall survival (OS) in Arm A versus a prespecified 40% historical benchmark; no between-arm comparison was planned. Results: Among 176 patients, 117 were assigned to Arm A and 59 to Arm B. Eighteen-month OS was 53.8% (95% CI, 44.3–62.5) and 65.7% (95% CI, 52.0–76.3), respectively. Baseline plasma profiling provided contributory information in 32 of 35 patients with noncontributory or unavailable tissue, increasing genotyping success from 69% to 97%. Paired baseline and early on-treatment samples were available in 90 patients (median, 21 days; range, 19–64). ctDNA clearance was associated with higher objective response rate (83% vs. 52%), longer progression-free survival (22.9 vs. 5.4 months; P<0.001), and longer OS (not reached vs. 17.1 months; P=0.004) than persistent detection. Conclusions: Serial ctDNA profiling with weekly MTB review was operationally feasible and complemented tissue genotyping. Clinical benefit was not demonstrated; early ctDNA kinetics require validation in interventional trials.