Predictors of Hepatotoxicity in Patients with Metastatic Solid Tumors Treated with Immune Checkpoint Inhibition (ICI) and Liver-Directed SBRT.

PURPOSE/OBJECTIVE(S): Liver-metastasis-directed SBRT (LM-SBRT) alone provides durable local control for liver metastases with low rates of toxicity when adhering to established dose constraints. Whether these constraints are sufficient in the context of concurrent ICI is not established. To determine whether LM-SBRT contributes to hepatotoxic adverse events (HAE) in patients receiving ICI, we analyzed potential predictors of HAE in a prospectively evaluated cohort of clinical trial patients treated with both SBRT and ICI.

MATERIALS/METHODS: Patients with metastatic solid tumors were included from three trials of multi-site SBRT with ICI given concurrently or shortly after SBRT provided they received all study treatments and were monitored for adverse events. ICI agents included pembrolizumab alone or dual agent ICI with nivolumab and either cabiralizumab, urelumab, or ipilimumab. LM-SBRT was delivered to 45 Gy in 3 fr with mean liver dose (MLD) limited to 16 Gy and <700 cc of liver receiving 17.1 Gy. HAE were defined using CTCAE 4.0 as: elevation of AST, ALT, bilirubin or alkaline phosphatase; autoimmune hepatitis; hepatic failure; or cholecystitis. HAE were included if rated at least possibly related to treatment by the trial monitoring committee. Cumulative incidence (CI) of HAE was modeled with death as a competing risk. Competing risks regression was performed using Fine-Gray modeling.

RESULTS: Two hundred thirteen patients were evaluable. Median follow-up was 10 months. Median age was 61, 90 had liver metastases at treatment, 65 received SBRT to a liver lesion, 15 had underlying liver disease (cirrhosis or hepatic steatosis) and 13 patients had a primary liver cancer. Dual agent ICI was given to 97 patients. Table 1 shows CI at 6 months of grades 1-4 HAE in all patients, LM-SBRT patients and non-liver SBRT patients (NL-SBRT). None experienced grade 5 HAE. There was no significant difference in CI of any grade of HAE between LM-SBRT and NL-SBRT patients. This was also true when comparing LM-SBRT patients to NL-SBRT patients with <0.1 Gy MLD. ICI dose reduction or cessation due to HAE occurred in 4 patients, none of whom received LM-SBRT. On univariate analysis, underlying liver disease and dual agent ICI were significantly associated with grade 2+ HAE while age, LM-SBRT, MLD, primary liver cancer and presence of liver metastases at treatment were not. On multivariate analysis, underlying liver disease and dual agent ICI remained significantly associated with grade 2+ HAE (HR: 6.7, 95% CI 2.3 - 19.1; 4.7, 95% CI 1.7 - 13.0). LM-SBRT and MLD were not significant on MVA.

CONCLUSION: LM-SBRT did not significantly increase the risk for hepatotoxicity in patients receiving ICI when respecting the above dose constraints. Risk for hepatotoxicity appears to be driven by dual agent ICI and underlying liver disease.