BACKGROUND: Standard treatment for unresectable stage III non-small cell lung cancer (NSCLC) involves chemoradiation (CRT) followed by PD-L1 targeting immune checkpoint inhibition (IO). Integrating 18 F-fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT into radiotherapy planning reduces toxicity, improves CRT outcomes, and potentially enhances immunotherapy response. Hypofractionated, accelerated CRT shortens treatment time, improves compliance, and may increase CRT completion rates, qualifying more patients for consolidative IO. METHODS/DESIGN: PACCELIO is a multinational, multicenter, randomized, phase II trial comparing the safety and efficacy of FDG-PET/CT based, volume-reduced, hypofractionated CRT with consolidation durvalumab to standard-volume, conventionally fractionated CRT with consolidation durvalumab in inoperable stage III NSCLC. One hundred and ten patients will be enrolled in Germany, Austria, and Switzerland, randomized 1:1, stratified by age, NSCLC stage, and site. The primary objective is to increase completion of CRT with successful transition to consolidation immunotherapy. Secondary outcomes include locoregional and distant tumor control rates, overall survival, safety, and health-related quality of life (HR-QoL). Exploratory outcomes involve prognostic immunomarkers and PET parameters. The primary endpoint of treatment completion will be analyzed using Fisher's Exact test, with safety and efficacy outcomes analyzed via Kaplan-Meier. DISCUSSION: The PACCELIO trial addresses a clinical need in stage III NSCLC by combining FDG-PET/CT based RT volume reduction with hypofractionated accelerated CRT and durvalumab immunotherapy. This approach aims to improve treatment completion, compliance, tumor control, and reduce toxicity. The trial will provide insights into the efficacy and safety of this combined treatment, potentially influencing future standards in stage III NSCLC treatment. Recruitment began in July 2024, with ongoing enrollment. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT06102057 (Date of initial registration: 26th October 2023), https://clinicaltrials.gov/study/NCT06102057. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-026-15901-x.
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