Immune checkpoint inhibitor rechallenge in advanced NSCLC: prognostic value of the neutrophil-to-lymphocyte ratio.

Background: Immune checkpoint inhibitor (ICI) rechallenge is increasingly used as a salvage strategy for advanced non-small cell lung cancer (NSCLC), but reliable prognostic biomarkers for patient selection remain undefined. This study aimed to identify clinically practical prognostic biomarkers for outcomes after ICI rechallenge in metastatic or recurrent NSCLC. Methods: We conducted a single-center retrospective study of patients with metastatic or recurrent NSCLC who had discontinued initial ICI owing to disease progression or immune-related adverse events (irAEs) and subsequently received ICI rechallenge, including cases between August 2017 and September 2023, with follow-up data collected through November 2024. The primary objective was to identify prognostic blood-based biomarkers, with a particular focus on the neutrophil-to-lymphocyte ratio (NLR). Clinical data, efficacy outcomes, and routine laboratory markers were analyzed. Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier estimates, with between-group comparisons performed by log-rank tests and hazard ratios (HRs) derived from Cox models. To further explore dynamic changes, paired biomarker levels at initial ICI and at rechallenge were compared using the Wilcoxon signed-rank test. Results: Thirty-three patients were analyzed. During initial ICI, the objective response rate (ORR) was 45.5%, with a median PFS of 8.1 months and a median OS of 28.3 months. In contrast, at rechallenge, the ORR declined to 12.1%, with a median PFS of 2.2 months and a median OS of 6.6 months. At rechallenge, NLR <4 was significantly associated with longer PFS (HR 0.30; P=0.01) and OS (HR 0.25; P=0.001) in univariate analysis and remained independently predictive of OS in multivariate analysis (HR 0.32; P=0.02). In the explanatory analysis, systemic inflammation changed between initial and rechallenge, with increases in NLR, monocyte-to-lymphocyte ratio (MLR), and systemic inflammation response index (SIRI), and decreases in serum albumin and prognostic nutritional index (PNI). As safety, irAEs occurred in 33.3% during rechallenge, most commonly pneumonitis (12.1%); one treatment-related death was observed. Conclusions: ICI rechallenge yielded modest efficacy in a heavily pretreated cohort. NLR at ICI rechallenge emerged as a simple, reproducible prognostic factor for PFS and OS, warranting validation of prespecified cut-offs and assessment within composite inflammation/nutrition scores in prospective multicenter studies.