Impact of Immune Checkpoint Inhibitors on Second Primary Cancer Risk in Patients With Metastatic Lung Cancer Using Real-World Data From the TriNetX Network: Retrospective Cohort Study

Abstract Background Survivors of metastatic lung cancer (MLC) face a heightened risk of developing second primary cancers (SPCs), which significantly impact long-term outcomes. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, but their potential role in reducing SPC risk remains underexplored. This study investigates the association between ICI treatment and the incidence of SPCs in a large, real-world cohort of patients with MLC. Objective This study aims to evaluate whether treatment with ICIs is associated with a reduced risk of developing SPCs in patients with metastatic or locally advanced lung cancer, using real-world data from the TriNetX global health research network. Methods We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, which aggregates deidentified electronic health records from more than 135 million patients. Adults diagnosed with MLC between February 2004 and February 2024 were included. Patients were divided into 2 cohorts based on ICI exposure. Propensity score matching was applied to balance baseline characteristics. Kaplan-Meier survival analysis and Cox proportional hazards models were used to assess the incidence of SPCs and the composite outcome of SPC or death. Results Among 2844 eligible patients, 685 received ICIs and 2157 did not. After propensity score matching, both cohorts included 685 patients. The 5-year incidence of SPCs was lower in the ICI group (1.5%) compared to the non-ICI group (4.2%), with a hazard ratio of 0.49 (95% CI 0.24‐1.01), suggesting a potential protective effect. Furthermore, ICI treatment was significantly associated with a reduced risk of the composite outcome of SPC or death (hazard ratio 0.74, 95% CI 0.62‐0.89). Median follow-up was 20.2 (IQR 60-not reached) months for the ICI group and 68.4 (IQR 36-not reached) months for the non-ICI group. Conclusions In this large real-world cohort, ICI treatment was associated with a lower risk of developing SPCs and improved overall outcomes in patients with MLC. These findings support the hypothesis that ICIs may offer a preventive benefit beyond their primary oncologic indications. While the retrospective nature and data limitations warrant cautious interpretation, this study underscores the value of real-world evidence in identifying novel therapeutic benefits and guiding future prospective research.