Circulating Tumor DNA Clearance Boosts Survival in Resectable Lung Cancer – NeoCOAST-2 Findings

In the phase‑2 NeoCOAST‑2 platform trial, researchers reported that adding the antibody‑drug conjugate datopotamab deruxtecan (Dato‑DXd) to standard chemotherapy plus durvalumab (anti‑PD‑L1) produced the highest pathological complete response (pCR) and event‑free survival (EFS) rates among patients with resectable stage IIA–IIIB non‑small cell lung cancer (NSCLC). The study enrolled four arms; Arm 4 (chemo + durvalumab + Dato‑DXd) included 54 patients and achieved a pCR of 35.2 % and a 24‑month EFS of 77.9 %. By contrast, Arm 1 (chemo + durvalumab + oleclumab) and Arm 2 (chemo + durvalumab + monalizumab) recorded pCRs of 20.3 % and 25.7 % and 24‑month EFS rates of 70.5 % and 75.7 % respectively. Using a tumour‑agnostic circulating tumour DNA (ctDNA) assay, clearance at neoadjuvant Cycle 3 Day 1 was observed in 72.5 % of Arm 4 patients, versus 50.9 % and 54.5 % in Arms 1 and 2. Investigators highlighted that ctDNA clearance correlated strongly with prolonged EFS (pooled hazard ratio 0.22, 95 % CI 0.11–0.45, P = 0.0000443). Moreover, patients who achieved both ctDNA clearance and pCR enjoyed an even more favorable outcome (EFS hazard ratio 0.10, 95 % CI 0.02–0.42, P = 0.002). “These dual biomarkers provide a powerful tool for early risk stratification,” said senior author Tina Cascone. The findings suggest that integrating ctDNA dynamics with pathological response could refine peri‑operative decision‑making, potentially sparing low‑risk patients from overtreatment while escalating therapy for those with residual disease. Nonetheless, the authors caution that longer follow‑up and larger phase‑3 studies are needed to confirm durability of benefit and to assess safety of the Dato‑DXd combination. If validated, the Dato‑DXd regimen may reshape the standard of care for resectable NSCLC, ushering a new era where molecular clearance guides surgical timing and adjuvant strategies, and where personalized oncology moves from concept to routine practice.