CMP Journal 2026-10-25

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Nature: 1

Nature

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

Original Paper | Non-small-cell lung cancer | 2026-10-24 20:00 EDT

Lara McGrath, Gozde Kar, Laura Bonanno, Florian Guisier, Amelia Insa, Moishe Liberman, Olivier Bylicki, Lorenzo Livi, Thomas Egenod, Romain Corre, Dong-Wan Kim, Maria Rosario Garcia Campelo, Mariano Provencio Pulla, Byoung Yong Shim, Giulio Metro, Jaafar Bennouna, Agata A. Bielska, Alula R. Yohannes, Joanna Shaju, Yun He, Adam Dowson, Italia Grenga, Jonathan Spicer, Patrick M. Forde, Tina Cascone

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.

Nature (2026)

Non-small-cell lung cancer, Cancer immunotherapy, Targeted therapies