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 treatment1-3. 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.

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Authors and Affiliations

  1. Translational Medicine, Oncology R&D, AstraZeneca, Cambridge, MA, USA

  2. Translational Medicine, Early Data Science, Oncology R&D, AstraZeneca, Cambridge, UK

  3. Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy

  4. Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy

  5. Univ Rouen Normandie, LITIS Lab QuantIF team EA4108, CHU Rouen, Department of Pneumology and Inserm CIC-CRB 1404, Rouen, France

  6. Medical Oncology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain

  7. Division of Thoracic Surgery, University of Montréal, Montréal, Quebec, Canada

  8. CETOC - CHUM Endoscopic Tracheobronchial and Oesophageal Center, Centre Hospitalier de l’Université de Montréal, Montreal, Quebec, Canada

  9. Pneumology Department, Hôpital d’Instruction des Armées Sainte-Anne, Toulon, France

  10. Department of Radiation Oncology, University of Florence, Florence, Italy

  11. Department of Thoracic Oncology, Dupuytren University Hospital, Limoges, France

  12. Department of Medical Oncology, CH de Cornouaille, Quimper, France

  13. Department of Internal Medicine, Seoul National University College of Medicine and Seoul National Hospital, Seoul, South Korea

  14. Hospital de A Coruña, Sergas, A Coruña, Spain

  15. Puerta de Hierro University Hospital, Majadahonda, Spain

  16. Department of Medical Oncology, The Catholic University of Korea, St. Vincent’s Hospital, Seoul, South Korea

  17. Santa Maria della Misericordia Hospital, University of Perugia, Perugia, Italy

  18. Department of Medical Oncology, Hôpital Foch, Suresnes, France

  19. Early Clinical Development, Oncology R&D, AstraZeneca, Cambridge, MA, USA

    Agata A. Bielska & Italia Grenga

  20. Early Clinical Development, Oncology R&D, AstraZeneca, Gaithersburg, MD, USA

    Alula R. Yohannes & Joanna Shaju

  21. Early Oncology Biometrics, Oncology R&D, AstraZeneca, Cambridge, MA, USA

  22. Early Clinical Programs, Oncology R&D, AstraZeneca, Cambridge, UK

  23. Department of Thoracic Surgery, McGill University, Montreal, Quebec, Canada

  24. Trinity St. James’s Cancer Institute, School of Medicine, Trinity College Dublin, Dublin, Ireland

    Patrick M. Forde

  25. Department of Thoracic-Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Corresponding author

Correspondence to Tina Cascone.

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This file contains the following items: Institutional review board and ethics committee approvals; Supplementary Figs. 1-3; and Supplementary Tables 1-6.

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McGrath, L., Kar, G., Bonanno, L. et al. ctDNA clearance and outcomes for resectable lung cancer from NeoCOAST-2. Nature (2026). https://doi.org/10.1038/s41586-026-11328-3

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