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Background Single-agent immune checkpoint inhibitors (ICI) is the standard treatment for patients with metastatic non-small-cell carcinoma (mNSCLC) without targetable driver mutations and high PD-L1 expression. According to literature data, high tumor burden (HTB) at diagnosis may serve as a negative predictive factor of response to mono-immunotherapy, however its role has not been validated.Methods This retrospective study included patients with mNSCLC and PD-L1≥50% treated with 1st line PD-1 or PD-L1 inhibitors (i) at the Careggi University Hospital from June 2017 to December 2024. HTB was defined by at least one of the following: sum of the longest diameter of target lesions or a primary tumor with a diameter of ≥10 cm, an increase of LDH ≥ 2 upper limit of normal, hepatic involvement, lymphangitis, pericardial effusion, brain involvement without indication for locoregional treatment, or any oncological emergency. Primary endpoints were progression free survival (PFS) and overall survival (OS).Results Out of 161 patients treated, 136 were included in the analysis. HTB was found in 80 (58.8%) patients and low tumor burden (LTB) in 56 (41.2%). The two groups presented similar baseline characteristics ( table 1).No statistical differences in PFS or OS were found between PD-L1 ≥80% and those with a lower PD-L1 expression. Patients with LTB significantly benefited from ICI vs HTB in terms of both median PFS (19.61 vs 3.09 months, HR 2.76, 95% CI: 1.82-4.40, p<0.001) and median OS (40.48 vs 4.34 months, HR 2.99, 95% CI: 1.93-4.62, p<0.001).Conclusions Our data support the idea of HTB as a negative predictor of response to mono-immunotherapy in mNSCLC with a PD-L1 ≥ 50%. The identification of this subgroup of patients could be useful to define and optimize a more aggressive treatment strategy.Ethics Approval The study obtained ethics approval. Participants gave informed consent before taking part.Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.Abstract 509 Table 1Baseline characteristics