Concurrent nivolumab and external beam radiation therapy for hepatocellular carcinoma with macrovascular invasion: A phase II study

Background and AimsNivolumab is the first immune checkpoint inhibitor for hepatocellular carcinoma (HCC). External beam radiation therapy (EBRT) is locally effective and may enhance the effectiveness of immunotherapy. This study investigated the efficacy and safety of concurrent nivolumab and EBRT in HCC with macrovascular invasion.MethodsIn this phase 2 multicenter trial, HCC patients with macrovascular invasion were concurrently treated with intravenous nivolumab (3 mg/kg every 2 weeks) and EBRT, followed by maintenance nivolumab until progression or unacceptable toxicity. Primary endpoints were progression-free survival (PFS) and safety, and secondary endpoints were overall survival (OS), time-to-progression (TTP), objective response rate (ORR), and disease control rate (DCR).ResultsBetween January 2020 and June 2021, 50 patients (male 84%, median age 62.5) were enrolled; 47 (94.0%) and 13 (26.0%) with portal (Vp1/2, n=21; Vp3, n=23; Vp4, n=3) and hepatic vein invasion, respectively. Patients received EBRT [median dose: 50 (interquartile range: 43–50) Gy] after the first nivolumab dose. The median number of nivolumab doses was 8.5. Median PFS was 5.6 (90% confidence interval [CI] 3.6–9.9) months. Median OS and TTP were 15.2 (90% CI 10.8–19.6) and 5.6 (90% CI 3.6–9.9) months, respectively. The ORR and DCR were 36.0% and 74.0%, respectively. The median duration of response was 9.9 months. Of 35 patients with follow-up data, 23 received subsequent systemic treatment, including atezolizumab-bevacizumab, sorafenib, lenvatinib, and regorafenib. Treatment-related any-grade AEs and grade 3/4 occurred in 40 (80.0%) and 6 (12.0%) patients, respectively. Common treatment-related AEs included pruritus (38.0%) and rash (16.0%), with no treatment-related deaths.ConclusionConcurrent nivolumab therapy and EBRT showed encouraging PFS with acceptable safety in advanced HCC patients with macrovascular invasion.Impact and Implications/Lay SummaryImmune checkpoint inhibitors (ICIs), the standard care for advanced hepatocellular carcinoma (HCC), show relatively poor therapeutic effects in advanced HCC patients with macrovascular invasion (MVI). In this investigator-initiated phase 2 study, we, for the first time, show that concurrent external beam radiation therapy with nivolumab, an ICI, showed encouraging progression-free survival in HCC patients with MVI. The concurrent treatment was tolerable without significant safety concerns. Further randomized studies investigating the combination of immunotherapy and EBRT are required.ClinicalTrials.gov identifierNCT04611165.