Abstract
OBJECTIVE: Combined modality treatment with chemotherapy, radiotherapy, and immunotherapy is a crucial therapeutic approach for lung cancer. However, controversies still exist regarding radiation doses, treatment regimens, and the risk of pneumonitis. This study aimed to conduct a comprehensive meta-analysis and in-depth subgroup analyses based on randomized controlled trials (RCTs) involving lung cancer patients undergoing radiotherapy to assess whether its combination with immunotherapy is effective and safe. METHODS: We systematically searched PubMed, Cochrane Central, Embase, and major conferences for randomized trials evaluating immune checkpoint inhibitors (ICIs) plus radiotherapy in lung cancer. The outcomes included progression-free survival (PFS), overall survival (OS), and the incidence of adverse reactions, particularly focusing on pneumonitis/pneumonia. Subgroup analyses were performed based on radiotherapy modalities, the timing of ICIs treatment, tumor stage, pathological type, and types of ICIs. RESULTS: Fifteen trials were included in this analysis. The addition of ICIs to radiotherapy or chemoradiotherapy significantly improved PFS (HR = 0.76, 95% CI 0.70-0.83) and OS (HR = 0.83, 95% CI 0.75-0.92). In subgroup analyses, stereotactic body radiotherapy (SBRT) (HR = 0.38, 95% CI 0.19-0.75) and hypo-fractionated radiotherapy (Hypo-RT) (HR = 0.49, 95% CI 0.31-0.79) were associated with improved PFS. Consolidation ICIs treatment improved OS (HR = 0.68, 95% CI 0.59-0.79), while concurrent ICIs had no significant effect (HR = 1.06, 95% CI 0.87-1.28). In terms of tumor stage, Stage I NSCLC patients (HR = 0.38, 95% CI 0.19-0.75) showed significant PFS improvement with ICIs. Both PD-1 (HR = 0.39, 95% CI 0.22-0.69) and PD-L1 (HR = 0.75, 95% CI 0.64-0.87) inhibitors were linked to improved PFS in irradiated lung cancer patients, and PD-L1 also enhanced OS (HR = 0.82, 95% CI 0.68-0.99). The addition of ICIs increased the risk of any-grade pneumonitis/pneumonia (RR = 1.27, 95% CI 1.12-1.44) but did not elevate the risk of severe (grade ≥3) events (RR = 1.12, 95% CI 0.78-1.60). Notably, among patients treated with SBRT, no significant increase was observed in the incidence of pneumonitis of any grade. CONCLUSIONS: PD-1/PD-L1 inhibitors combined with radiotherapy especially SBRT can enhance survival outcomes in lung cancer without increasing the risk of severe pneumonitis/pneumonia, supporting their clinically manageable safety profile. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/home, identifier CRD420251140111.