This 20-year narrative review covers the evolution of immune checkpoint inhibitor (ICI) therapy in lung cancer—both NSCLC and SCLC—across all disease stages, from second-line monotherapy through perioperative strategies, including biomarkers, resistance mechanisms, toxicity, and emerging immunotherapeutic approaches.
ICIs have transformed lung cancer outcomes across stages: 5-year OS reached 31.9% with first-line pembrolizumab in PD-L1 ≥50% NSCLC (KEYNOTE-024) vs. ~5% historically; perioperative pembrolizumab (KEYNOTE-671) yielded the first mature OS benefit in resectable NSCLC; consolidation durvalumab in unresectable stage III NSCLC (PACIFIC) achieved 42.9% 5-year OS vs. 29.1% for placebo; and in ES-SCLC, chemoimmunotherapy improved median OS by ~2–5 months (e.g., 12.3 vs. 10.3 months in IMpower133), though long-term survivors remain rare.
- Entirely a narrative review; no primary data, meta-analysis, or systematic evidence synthesis—subject to selection bias in trial coverage. - Key outstanding questions (optimal ICI duration beyond 2 years, MRD-guided treatment decisions, best strategies for oncogene-driven NSCLC) remain unresolved due to lack of prospective randomized data. - Underrepresentation of older adults, patients with comorbidities, and low/middle-income populations in the cited trials limits generalizability.
PD-L1 testing should guide first-line ICI selection in advanced NSCLC, with monotherapy favored at ≥50% and chemo-IO combinations appropriate across all expression levels; stopping ICI at 2 years appears safe based on current retrospective data, though prospective confirmation is lacking. In oncogene-driven NSCLC (EGFR, ALK, RET, ROS1), ICIs offer limited benefit and carry serious safety risks when combined with TKIs—targeted therapy-first strategies should be prioritized and concurrent TKI-ICI use avoided outside clinical trials.
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