Treatments for invasive T₄ non-small cell lung cancer (NSCLC) tumors have been traditionally individualized and often require multidisciplinary team (MDT) evaluation. Advances in precision medicine may open up new opportunities for these patients.

This retrospective cohort study, using the Surveillance, Epidemiology, and End Results (SEER) database, identified T₄N_0-3M₀ NSCLC patients with central structure invasion from 2010 to 2020. Precision medicine has progressed in three periods: 2010–2014 (targeted therapy), 2015–2017 (initial immunotherapy), and 2018–2020 (latest immunotherapy). We utilized Propensity Score Matching (PSM) to control confounding factors and competing risk regression models to evaluate cancer-specific survival (CSS).

A total of 9,106 cases were matched after PSM. For all populations, the median overall survival (OS) significantly increased with the advancement of precision medicine: 23.0 months in Period I (95 ​% CI: 22.0–25.0), 28.0 months in Period II (95 ​% CI: 26.0–31.0), and not reached (NR) in Period III (95 ​% CI: 30.0 – NR). Multivariate analysis also revealed a sequential survival improvement from Period I to III (p ​< ​0.001). Surgery-based treatment yielded the longest median OS at 46.0 months (95 ​% CI: 43.0–49.0, p ​< ​0.001), compared with chemoradiotherapy, chemotherapy alone and radiation alone. Surgery-based treatment has also yielded the best survival in three precision medicine eras, in both N_0-1 and N_2-3 categories. After analyzing CSS, the results above remained consistent. The survival following chemoradiotherapy and chemotherapy alone has seen significant and progressive enhancements across the three eras of precision medicine. There were no significant survival differences between Periods I and II among surgery-based patients, but a slight improvement trend was noted in Period III.

This retrospective study indicated that as precision medicine for NSCLC evolved, personalized treatment strategies supported by effective MDT led to survival improvement. Notably, for invasive stage III patients, surgery-based strategies have consistently shown substantial benefits across all the periods, irrespective of the N stage. The integration of perioperative therapies to enhance surgical feasibility, especially the latest immunotherapy, holds particular promise for further survival benefits.