Background: ctDNA shed is a promising biomarker for cancer immunotherapy, with patients (pts) having higher concentration of plasma ctDNA being reported to have poorer outcome. Its role in the maintenance setting with immune checkpoint inhibitors remains unexplored. In SAFIR02-Lung, advanced NSCLC pts were enrolled to receive a platinum-based chemotherapy. After 4 cycles, if stable or in response, pts with no targetable alterations were oriented to the immunotherapy sub-study and randomized between maintenance durvalumab or Standard of Care (SoC) (PMID 35802649). Durvalumab prolonged survival only in the PD-L1 ≥ 1% subgroup. Here we explored Tumor Fraction (TF) as determined by Low-Pass Whole Genome Sequencing as a biomarker for immunotherapy irrespective of PD-L1. Methods: SAFIR02-Lung (NCT02117167) is a multicentric, randomized phase 2 clinical trial. Plasma samples were obtained at randomization, just before maintenance treatment initiation. DNA was extracted using the Maxwell RSC ccfDNA Plasma Kit (Promega, AS1840). Sequencing libraries were prepared using the Low Input SureSelectXT protocol (Agilent, G9916A). Pooled libraries were sequenced on a NovaSeq 6000 platform (Illumina) as 2 × 150 bp paired-end reads (NovaSeq 6000 SP Reagent Kit v1.5). Genomic copy number aberrations and TF were investigated using the ichorCNA (V0.2.0) tool. TF ≥ 2% was considered positive. For the survival analyses, a landmark approach was performed, by considering the randomization date as the landmark time. Progression Free Survival (PFS) was the primary endpoint, defined as the time from randomization until the date of objective radiological disease progression, clinical progression or death. The secondary endpoint was Overall Survival (OS). Results: 50 out of 121 plasma samples from pts randomized to durvalumab were analyzed for the feasibility part. 34 pts (68%) were < 65 years, 33 (66%) were male. PD-L1 expression was available for 18 pts and 39% of them had PD-L1 ≥ 1%. Median TF was 1.1%, 8 pts (16%) had a TF ≥ 2%, ranging from 2.2% to 23.3%. TF at randomization was marginally correlated with the presence of liver metastases (p 0.063) and with the sum of target lesions (p 0.081). No significant correlation was observed with PD-L1 positivity. Pts with TF ≥ 2% had lower median PFS 1.7months (m) (95% CI 1.2 – 4.2) vs 5.8m (95% CI 2.9 – 7.5) for those with TF < 2%, p 0.0003. Similarly, median OS was lower for pts with TF > 2% 10.4m (95% CI 4.2 – 18.7) vs 25.9m (95% CI 18.2 – NR) for those with TF < 2%, p 0.0002. Data will be presented on the whole cohort, including control group receiving SoC, to discriminate between a prognostic or a predictive value of TF. Conclusions: TF was positive in 16% of pts randomized to durvalumab in the SAFIR02-Lung trial. This population seems to have a limited benefit from maintenance durvalumab after induction chemotherapy. Clinical trial information: NCT02117167.