| Sumario: | Simple Summary: Pembrolizumab combined with platinum-based chemotherapy is the standard first-line treatment for patients with metastatic non-squamous non-small-cell lung cancer (NSCLC) and intermediate PD-L1 expression (1–49%). However, treatment outcomes in routine clinical practice remain heterogeneous, and predictors of benefit are not well defined. In this real-world study from Serbia, we evaluated clinical outcomes and immune-related adverse events (irAEs) in patients treated with first-line pembrolizumab–chemotherapy. We found that patients who developed skin or thyroid irAEs experienced longer progression-free survival. These findings suggest that certain low-grade, manageable immune toxicities may reflect effective immune activation and could serve as practical on-treatment markers of benefit in patients receiving chemo-immunotherapy. Background: Pembrolizumab combined with pemetrexed–platinum chemotherapy is the standard first-line treatment for patients with metastatic non-squamous non-small-cell lung cancer (NSCLC) and a PD-L1 tumor proportion score (TPS) of 1–49%. Real-world data on treatment outcomes and the prognostic relevance of immune-related adverse events (irAEs) in this population remain limited, particularly in Eastern Europe. Methods: We conducted a retrospective, single-center real-world study including patients with metastatic non-squamous NSCLC and PD-L1 TPS of 1–49% treated with first-line pembrolizumab plus pemetrexed–platinum chemotherapy between June 2024 and May 2025. Progression-free survival (PFS) was estimated using the Kaplan–Meier method. Cox proportional hazards models were used to evaluate factors associated with PFS, including baseline clinical characteristics and organ-specific irAEs graded according to CTCAE v5.0. Results: A total of 107 patients were included. Median PFS for the entire cohort was 7.03 months (95% CI, 4.81–9.26). Immune-related adverse events occurred in 52 patients (48.6%), with thyroid (21.5%) and skin (13.1%) irAEs being the most frequent. The majority of irAEs were grade 1–2, while grade 3–4 events were rare (4.7%) and limited to hepatic toxicity and pneumonitis, all leading to treatment discontinuation. In multivariate analysis, ECOG performance status 2 was independently associated with inferior PFS (HR 3.09, 95% CI 1.74–5.48; p < 0.001). Conversely, the occurrence of thyroid irAEs (HR 0.36, 95% CI 0.17–0.78; p = 0.009) and skin irAEs (HR 0.28, 95% CI 0.10–0.79; p = 0.016) was independently associated with prolonged PFS, whereas pulmonary, hepatic, and gastrointestinal irAEs were not. Conclusions: In this real-world cohort of patients with metastatic non-squamous NSCLC treated with first-line pembrolizumab–chemotherapy, clinical outcomes were consistent with prior real-world experience. These findings suggest that low-grade, manageable immune toxicities may serve as pragmatic on-treatment markers of benefit. However, given the retrospective design, limited sample size, and the absence of time-dependent analyses, these associations should be interpreted with caution and considered hypothesis-generating rather than causal.
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