Serial ctDNA genomic profiling integrated with a networked molecular tumor board in first-line advanced NSCLC: The COPE randomized phase II trial.

8551 Background: Circulating tumor DNA (ctDNA) complements tissue profiling and may provide early response information in advanced NSCLC, but prospective evidence is limited. Methods: COPE is an open-label, multicenter, randomized (2:1), two-arm non-comparative phase II trial in stage IIIB/IV NSCLC (NCT04258137). Arm A included FoundationOneLiquidCDx ctDNA profiling at baseline, week 3, each radiologic assessment, and progression with centralized molecular tumor board (MTB) review; Arm B used baseline tissue profiling and standard imaging. ctDNA-guided treatment changes were discretionary. The primary endpoint was18-month (mo) overall survival (OS) rate in Arm A vs a prespecified historical benchmark; secondary/exploratory endpoints included profiling success, objective response rate (ORR), ctDNA dynamics, and genomic evolution. Results: From 2020–2023, 176 patients (pts) were enrolled (Arm A n = 117; Arm B n = 59). At median follow-up 24.0 mo, 18-mo OS was 53.8% (95% CI 44.3–62.5) in Arm A (median OS 22.4 mo) and 65.7% (95% CI 52.0–76.3) in Arm B. Baseline plasma profiling rescued genotyping in 32/35 pts with tissue insufficiency, increasing genotyping success from 69% (tissue alone) to 97% (tissue + plasma). In Arm A, 90/117 had evaluable paired baseline and week-3 plasma samples. Among pts receiving first-line (1L) chemo-immunotherapy (chemo + ICI), early molecular response (MR), defined as ctDNA no longer detected at day 21 was strongly associated with more favorable outcomes, including higher ORR (81.8% vs 50.0%), longer progression-free survival (median PFS 22.9 vs 5.9 mo), and OS (18-mo OS 81.8% vs 57.1%). Similar results were observed in the overall study population. MR50, defined as ≥50% reduction at day 21, showed similar associations with more favorable outcomes. In pts on chemo + ICI with further ctDNA testing, those with durable MR50 through mo 5-9 had longer mPFS (23 mo vs 11 mo), similar to pts with early ctDNA clearance. Importantly, excluding pts who progressed at/before week 3, the median lead time in detecting progression on chemo + ICI with ctDNA prior to radiographic progression was 3.5 mo (N = 19pts). Among 59 responders with paired baseline and any on treatment plasma, 35 were treated with 1L chemo + ICI and 13 with 1L targeted therapy. Tumor-associated emergent alterations were detected in 37 pts (63%), with treatment-specific resistance patterns observed across therapeutic classes. Conclusions: COPE is, to our knowledge, the first randomized prospective study of sequential ctDNA profiling in 1L advanced NSCLC. Serial ctDNA analysis within a networked MTB model was feasible, improved baseline molecular profiling, and provided a strong exploratory early molecular response signal, supporting future ctDNA-guided interventional trials. Clinical trial information: NCT04258137 .