Off-label Use of Nivolumab Beyond First-Line in Advanced Hepatocellular Carcinoma: a Report of Two International Experiences

Investigational use of nivolumab as first-line therapy for the treatment of hepatocellular carcinoma (HCC) yielded promising results but not enough to be introduced in guidelines. Limited data exists on its use beyond first-line.Aims: to evaluate the efficacy and safety of nivolumab as monotherapy beyond first-line in patients with HCCMethods: we analyzed data from consecutive HCC patients, ineligible for any other therapy, receiving off-label nivolumab at two referral centers in Italy and Germany between May-2016 and October-2023.Measured outcomes were overall survival (OS), progression-free survival (PFS), disease-control-rate (DCR), biological response (BR), defined as an ≥25% decrease in alpha-fetoprotein (AFP) level after 3 months of therapy, and adverse events.Results: 30 patients were enrolled (Italy n=24, Germany n=6). Patient characteristics were as follows: median age 65 (range 30-82) years, Child-Pugh A-B 80%-20%, BCLC B-C 13%-87%. One patient received nivolumab as I-line, 19 as II-line, 8 as III-line, and 2 as IV-line.Median OS was 9.1 (95%CI 6.4-14.2) months and median PFS was 3.5 (95%CI 2.8-6.4) months. At 3 months, DCR was 27% (8/30) and BR was obtained in 23% (7/30) of patients. Two patients achieving complete radiologic response.Median OS in patients with radiological disease control at 3 months was 27.7 (95%CI 4.7-41.2) months compared to 7.3 (95%CI 4.0-9.1) months in patients with disease progression (p<0.001). Median OS in patients with BR was 38.0 (95%CI 23.5-41.2) months compared to 7.8 (95%CI 3.6-12.1) months in patients without BR (p<0.001).At baseline, better performance status, presence of metastatic lymphnodes, AFP≥400 µg/L, and lower disease burden were associated with longer OS (all p<0.05).Grade 3-4 adverse events occurred in 10 patients (33%).Conclusion: nivolumab could represent a valuable option in patients without other alternatives, showing an OS greater than 6 months in 77% of patients and an acceptable safety profile. Radiological response at 3 months and BR predict a significantly longer survival.