A phase I study of nivolumab (NIVO) in combination with TheraSphere (Yttrium-90) in patients with advanced hepatocellular cancer.
Authors: Fenton Sarah Elizabeth , Kircher Sheetal Mehta , Mulcahy Mary Frances , Mahalingam Devalingam , Salem Riad , Lewandowski Robert , Kulik Laura , Benson Al Bowen , Kalyan Aparna 
Published: June 2021

e16183 Background: Significant advances have been made in the management of hepatocellular carcinoma (HCC) with the introduction of locoregional therapies including Theraspere, a treatment utilizing glass microspheres coated in radioactive yttrium-90 (Y-90). Hepatocyte exposure to Y-90 results in immunogenic cell death and tumor-specific immunity, suggesting this treatment may synergize with checkpoint inhibitor therapies to improve response rates and disease control. This abstract presents the results of combination therapy with Y-90 and NIVO in patients with advanced HCC. Methods: This study is a prospective, open-label, phase I clinical trial of NIVO plus Y-90. Eligible patients were diagnosed with advanced HCC (CP A6-B7) and were not transplant or resection candidates. Patients were treated with Y-90 following institutional procedures. The NIVO dose was escalated in a standard 3+3 format. Patients at DL1 began therapy 4 weeks after Y90 administration and received 80 mg of NIVO every two weeks. Patients at DL2 began therapy 2 weeks after Y90 administration and received 240 mg of NIVO every two weeks. The primary objective was to determine a maximum tolerated dose (MTD) of NIVO in combination with Y-90 therapy. Secondary objectives included objective response rate (RECIST v1.1), toxicity evaluation, disease control rate and progression free survival. Results: Fifteen patients were registered to DL1, 8 received Y90 and 6 were eligible and received NIVO. Twelve patients were registered to DL2, 9 were eligible for Y90, 7 were eligible for NIVO and 6 completed therapy. Patients that did not complete therapy either withdrew consent, had a decline in performance status or a worsening in hepatic function. Fifty-nine percent of patients were male (N = 10), 82% were Caucasian (N = 14), 12% were Hispanic or Latino (N = 2) and 6% were African American (N = 1). Of the patients who received both Y90 and NIVO, 82% patients were CP B7. The MTD of NIVO is 240mg given 2 weeks after Y90. The disease control rate was 82% (N = 9/11 with stable disease). Forty-six percent of patients (N = 6) had a decrease in circulating levels of AFP, the most significant change was a decrease from 11,080 ng/mL to 260 ng/mL following cycle 2 of NIVO and normalization by cycle 4 of NIVO. The most common toxicities in both treatment groups were Grade 1-2 elevations in ALT/AST, frequency of these side effects was not higher than expected given this patient population. Conclusions: Therapy with Y-90 and NIVO in advanced HCC was tolerable and a maximum tolerated dose of NIVO was established. Combination therapy resulted in a clinical benefit rate of 82%, with 9 patients achieving stable disease. In a notably sick patient population with advanced CP scores this combination offered good disease control without increasing the adverse event rate. Study was stopped early due to lack of funding. Clinical trial information: NCT02837029.