Definitive radiotherapy provides comparable survival with lower toxicity compared with concurrent chemoradiotherapy after long-course induction chemoimmunotherapy in unresectable non-small-cell lung cancer

Background: Long-course induction chemoimmunotherapy (⩾3 cycles) is increasingly used to downstage unresectable non-small-cell lung cancer (NSCLC). However, the optimal definitive local treatment for patients who remain inoperable after induction—definitive radiotherapy (RT) alone versus concurrent chemoradiotherapy (CRT)—remains unclear. Objectives: To compare survival and toxicity outcomes between definitive RT and CRT following induction chemoimmunotherapy in unresectable NSCLC. Design: This was a single-center retrospective cohort study using stable inverse probability of treatment weighting (sIPTW) to balance baseline characteristics between treatment groups. Methods: Consecutive patients with unresectable NSCLC without known actionable driver mutations who remained inoperable after long-course induction chemoimmunotherapy and subsequently received definitive RT or CRT were included. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan–Meier methods and compared with weighted Cox proportional hazards models. Treatment-related adverse events were graded according to the Common Terminology Criteria for Adverse Events. An exploratory analysis evaluated the association between consolidation immunotherapy and PFS. Results: A total of 153 patients were included (RT, n = 63; CRT, n = 90). At a median follow-up of 25.8 months, the 1- and 2-year PFS rates were 83.5% and 54.3% in the RT group, compared with 82.1% and 61.1% in the CRT group (hazard ratio (HR) = 0.83; 95% confidence interval (CI), 0.51–1.37; p = 0.46). After sIPTW adjustment, PFS remained comparable (HR = 0.80; 95% CI, 0.47–1.35; p = 0.46). OS was also similar between groups. Grade 3–4 hematologic toxicity was more frequent with CRT (24.4% vs 9.5%; p < 0.001). Consolidation immunotherapy was associated with a numerical but non-significant PFS improvement (HR = 0.78; 95% CI, 0.48–1.27; p = 0.32). Conclusion: In patients with unresectable NSCLC who remain inoperable after long-course induction chemoimmunotherapy, definitive RT alone provides survival outcomes comparable to CRT while reducing severe hematologic toxicity. RT alone may represent a reasonable definitive option for carefully selected patients in this setting.