Lung Immune Prognostic Index-Based Predictive Score in Advanced Non-Small Cell Lung Cancer with a Programmed Death Ligand-1 Tumor Proportion Score ≥ 50%

<b>Background/Objectives:</b> The Lung Immune Prognostic Index (LIPI) has emerged as a promising biomarker for predicting outcomes in advanced non-small cell lung cancer (aNSCLC). We assessed whether LIPI, in combination with baseline clinical characteristics, can guide first-line treatment selection between pembrolizumab (P) and pembrolizumab plus platinum-based chemotherapy (PCT) in patients with PD-L1 tumor proportion score (TPS) ≥ 50% and EGFR/ALK/ROS1 wild-type. <b>Methods:</b> A predictive score was developed using baseline clinical variables, including age, sex, smoking status, and LIPI, in a proof-of-concept cohort (n = 241). This model was then validated in an independent cohort of 409 patients. OS was compared between patients treated with P versus PCT, stratified by predictive score. <b>Results:</b> In the proof-of-concept cohort, the median OS was 18.3 months for P and 26.6 months for PCT (<i>p</i> = 0.001). In the validation cohort, the median OS was 28.0 months for P and 22.2 months for PCT (<i>p</i> = 0.062). Stratification using the predictive score showed that patients with high scores (3-5) had improved OS with PCT compared to P (31.2 vs. 25.5 months, <i>p</i> = 0.001), while those with low scores (0-2) derived similar benefits from both treatments. <b>Conclusions:</b> This LIPI-based predictive score may assist in identifying aNSCLC patients who derive greater benefit from chemo-immunotherapy over immunotherapy. Its simplicity and clinical relevance support integration into treatment decision-making, pending prospective validation.