ctDNA clearance and outcomes for resectable lung cancer from NeoCOAST-2

Patients with resectable non-small cell lung cancer (NSCLC) remain at high risk of relapse despite perioperative treatment^1-3. NeoCOAST-2 (NCT05061550), a phase 2, randomised platform trial, tested novel perioperative treatments in patients with stage IIA-IIIB NSCLC. At primary analysis, combining standard chemotherapy plus durvalumab (anti-PD-L1 antibody) with oleclumab (Arm 1, n = 76), monalizumab (Arm 2, n = 72) or datopotamab deruxtecan (Dato-DXd; Arm 4, n = 54) resulted in pathological complete response (pCR) rates of 20.3%, 25.7%, and 35.2%, respectively⁴. Here, we present the first report of prespecified secondary endpoints of event-free survival (EFS) and circulating tumour DNA (ctDNA) clearance, and exploratory analyses of associations between ctDNA dynamics and clinical outcomes. The 24-month EFS rates were 70.5%, 75.7% and 77.9% in Arms 1, 2 and 4, respectively. Using a tumour-agnostic assay, ctDNA clearance at neoadjuvant Cycle 3 Day 1 was highest in Arm 4 (50.9%, 54.5%, and 72.5% in each arm, respectively). ctDNA clearance correlated with prolonged EFS versus non-clearance (pooled hazard ratio (HR) 0.22; 95% CI = 0.11-0.45, P = 0.0000443). Patients with both ctDNA clearance and pCR had favourable EFS outcomes versus those with neither (EFS HR 0.10, 95% CI = 0.02-0.42, P = 0.002). These findings suggest combined assessment of ctDNA clearance and pCR may improve risk stratification, and that the numerically highest pCR⁴ and EFS rates with the Dato-DXd combination warrant further evaluation.