Combined Stereotactic Body Radiation Therapy and Immune Checkpoint Inhibition for Liver Metastases: Safety and Outcomes in a Pooled Analysis of 3 Phase 1 Trials

Purpose Stereotactic body radiotherapy (SBRT) safely and effectively controls liver metastases, but its safety and efficacy when combined with immune checkpoint inhibitors (ICIs) are not well characterized. This analysis of three phase I trials of combination SBRT and ICI evaluates whether liver metastasis SBRT (LM-SBRT) increases the risk for hepatotoxicity when combined with ICI and explores efficacy endpoints. Methods Data were analyzed from three phase I trials of combination SBRT and ICI for patients with metastatic solid tumors conducted between 2016 and 2020. ICI was administered per trial protocol with LM-SBRT delivered to 45 Gy in 3 fractions with mean liver dose <16 Gy and ≥700cc of normal liver spared 17.1 Gy. Hepatic adverse events (HAEs) were defined as hepatic failure; autoimmune hepatitis; or elevation of AST, ALT, bilirubin or alkaline phosphatase using CTCAE 4.0. Cumulative incidence of HAE and local failure were modeled with death as a competing risk. Competing risks regression was performed using Fine-Gray modeling. Survival was estimated by the Kaplan-Meier method. Results 200 patients were analyzed, including 81 patients with liver metastases, 57 of whom received LM-SBRT. The 12-month rate of any grade ≥2 HAE was 11% and 10% in LM-SBRT and non-LM-SBRT patients, respectively (NS). Radiographic evidence for liver disease and dual-agent ICI were significantly associated with HAEs on univariable and multivariable analysis while liver dose metrics were not. Patients with liver metastases had significantly worse progression-free and overall survival compared to those without and local failure of treated liver metastases was significantly higher than for treated extrahepatic metastases (28% vs 4% at 12 months, p < 0.001). Conclusions Combination LM-SBRT and ICI did not significantly increase the risk for HAE compared to ICI without LM-SBRT, suggesting hepatotoxicity is largely driven by factors other than liver RT such as choice of ICI. Liver metastasis is associated with worse overall survival and local control outcomes.