What is the optimal timing of radiotherapy and immunotherapy in lung cancer? A meta-analysis of randomized trials using reconstructed Kaplan–Meier data.

Abstract

e20076 Background: The increasing use of combined radiotherapy (RT) and immunotherapy (IO) in lung cancer is driven by evidence that RT can enhance immune activation by increasing neoantigen release, particularly when IO is given before RT. However, RT may also induce vascular damage and immunosuppressive changes that could reduce IO efficacy when administered after RT. These opposing effects create uncertainty regarding the optimal sequencing of RT and IO, supporting the need for systematic evaluation using randomized evidence. Methods: We searched PubMed, Web of Science, Scopus, and the Cochrane Library from inception through November 8, 2025, and evaluated overall survival (OS), progression-free survival (PFS), pneumonitis, and immune-related pneumonitis. Analyses were conducted in R using random-effects models, pooling categorical outcomes as risk ratios (RR) and time-to-event outcomes as hazard ratios (HR) with 95% confidence intervals (CI); when Kaplan–Meier curves (KM) were reported, individual patient data were reconstructed to generate pooled survival curves and study-stratified Cox models for comparisons across treatment strategies. Results: Across 20 randomised controlled trials including 4,309 patients, IO–RT–based combination therapy significantly improved PFS compared with monotherapy (HR 0.74, P < 0.01), with benefit mainly driven by regimens incorporating chemotherapy. The greatest PFS and overall survival benefits were observed when immunotherapy was administered after radiotherapy (PFS HR 0.67, P = 0.0024; OS HR 0.69, P = 0.0021), whereas no significant benefit was seen with prior or concurrent immunotherapy; subgroup differences by timing were significant for OS ( P < 0.0001). Combination therapy was associated with a higher risk of any-grade pneumonitis (RR 1.56, P = 0.01), but no significant increase was observed for grade 3–4 (RR 1.30, P = 0.25), grade 5 pneumonitis ( P = 0.16), or immune-related pneumonitis (any grade P = 0.07; grade 3–4 P = 0.91), with no effect of IO–RT sequencing. Reconstructed KM analyses showed that IO given before RT was associated with significantly worse PFS, while concurrent and post-RT IO had similarly improved PFS, with prior IO conferring markedly higher risk compared with concurrent (HR 5.16) or post-RT IO (HR 4.31) and no significant difference between concurrent and post-RT timing (HR 1.20). Conclusions: IO–RT–based combination therapy provides superior progression-free and overall survival compared with monotherapy, especially if associated with chemotherapy. The greatest benefit is observed when immunotherapy is administered after radiotherapy. Pneumonitis rates did not differ meaningfully between treatment approaches, and safety outcomes were comparable regardless of IO–RT sequencing.