Whether intensifying the radiotherapy dose for unresectable stage III NSCLC that is later managed with immunotherapy provides any advantage remains poorly understood. This analysis was designed to explore whether intermediate-dose escalation (IDE) yields a survival benefit in stage III NSCLC treated with definitive concurrent chemoradiation (dcCRT) and subsequent immunotherapy. The study extracted information from the National Cancer Database. All-cause mortality was evaluated through multivariable Cox regression, contrasting a standard RT dose (SD) (60 Gy ± 10%) against IDE (64–74 Gy). Within the pre-immunotherapy timeframe, 47,315 individuals were diagnosed and managed exclusively with dcCRT, while 4,947 received dcCRT in combination with immunotherapy. Among the dcCRT-only subset, SD was associated with a statistically significant increase in mortality but a clinically trivial difference compared with IDE (HR: 1.09, 95% CI: 1.07-1.12; P < 0.0001). During the immunotherapy period, SD remained associated with lower mortality than IDE (HR: 1.17, 95% CI: 1.03-1.33; P = 0.02). The survival benefit linked to IDE, however, applied exclusively to patients whose immunotherapy began within six weeks of completing RT (HR: 1.26, 95% CI: 1.05-1.6; P = 0.01). No mortality divergence emerged between SD and IDE for those starting immunotherapy at 7–10 weeks (HR: 1.13, 95% CI: 0.88-1.45; P = 0.35) nor for delays exceeding 10 weeks after RT completion (HR: 0.74, 95% CI: 0.51-1.07; P = 0.11). For stage III unresectable NSCLC patients who do not initiate immunotherapy more than 6 weeks after dcCRT, the IDE of RT is unwarranted.
