Phase 1 Randomized Trial of Stereotactic Body Radiation Therapy Followed by Nivolumab plus Ipilimumab or Nivolumab Alone in Advanced/Unresectable Hepatocellular Carcinoma

Purpose: Immunotherapy has emerged as a promising therapeutic option for advanced or unresectable hepatocellular carcinoma (HCC). However, survival remains poor with only a subset of patients deriving benefit. This trial investigated the safety and efficacy of stereotactic body radiation therapy (SBRT) with immunotherapy in HCC.Methods and Materials: In this multicenter phase 1 randomized trial, patients with advanced or unresectable HCC received liver SBRT (40 Gy in 5 fractions) followed by either nivolumab alone or nivolumab plus ipilimumab. The primary endpoint was dose-limiting toxicity occurring within 6 months of SBRT. Secondary endpoints included overall response rate, progression-free survival, overall survival (OS), distant disease control, and local control of the irradiated tumor. Disease status and response endpoints were assessed radiographically every 8 weeks until progression or initiation of nonprotocol therapy. Response was determined using both RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 and iRECIST.Results: Fourteen patients were enrolled across 3 centers. Thirteen patients were evaluated for study endpoints. The study was closed early because of slow accrual. The median follow-up time was 42.7 months. Dose-limiting toxicities within 6 months occurred in 2 (15.4%) of 13 patients: 1 of 6 patients in the nivolumab arm (16.7%; 90% confidence interval [CI], 0.9%-58.2%) and 1 of 7 patients in the nivolumab plus ipilimumab arm (14.3%; 90% CI, 0.7%-52.1%). Grade 3 adverse events occurred in 8 (61.6%), 5 (71.4%), and 3 (50.0%) patients in the overall nivolumab plus ipilimumab and nivolumab cohorts. Grade 3 hepatotoxicity occurred in 4 (30.8%), 3 (42.9%), and 1 (16.7%) patients in the respective cohorts. Clinical outcomes favored the nivolumab plus ipilimumab arm compared with nivolumab alone, including an overall response rate of 57% (4 of 7 patients; 90% CI, 23%-87%) versus 0% (0 of 6 patients; 90% CI, 0%-39%), median progression-free survival of 11.6 months (90% CI, 4.5 months to not reached) versus 2.7 months (90% CI, 1.3-4.7 months), and median OS of 41.6 months (90% CI, 4.5 months to not reached) versus 4.7 months (90% CI, 2.0-16.2 months) (all P < .05). With combination immunotherapy, 3-year OS was 57% (90% CI, 23%-81%), with 2 patients alive after 42.7 months without progression and negative PET.Conclusions: In this first prospective trial investigating the combination of SBRT and immunotherapy for HCC, multimodal therapy demonstrated acceptable safety. SBRT with nivolumab plus ipilimumab compared favorably to outcomes of immuno-therapy alone and warrants further investigation.