**3.6 Second-line immunotherapy**

Second-line therapy after the failure of sorafenib apart from molecular targeting agents. Data of immunotherapy both pembrolizumab (an anti-PD-1 monoclonal antibody) and nivolumab (a fully humanized monoclonal antibody against PD-1) shown efficacy in Phase Ib studies (CheckMate-040 [34] and Keynote-224 [35]). Unfortunately, for pembrolizumab, these results were negative in the Phase III study, randomized double-blind keynote-240 study, which included a total of 413 patients with pretreated advanced HCC. The study was comparable with pembrolizumab or placebo. The median OS was 13.9 months in the pembrolizumab arm versus 10.6 months in the control arm (HR: 0.78; *P* = 0.024), the median PFS was 3.0 mons versus 2.8 mons (HR: 0.72; *P* = 0.002). However, since the prespecified alpha level was significantly lower, the study must be considered statistically negative. CTLA-4 antibodies were also tested in second-line therapy of advance stage HCC; The study reported results (response rate was 17.6% and a median time to progression was 6.48 months) from patients treated with tremelimumab [36]. Nivolumab as single agent in advance HCC treated with sorafenib reported an ORR of 14% and median OS of 16 months. Due to the promising results the study was conducted

the efficacy and safety of the combination of nivolumab and ipilimumab [37]. The study was randomized into three different dose and time arms of nivolumab and ipilimumab. Of note, the first arm (Nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks (Q3W) followed by n 240 mg Q2W) demonstrated the most promising efficacy in term of OS (23 months). ORR and disease control rate were 31% and 49%, respectively. Interestingly, the different combinations were well tolerated, potentially offering a novel treatment option for patients with pretreated HCC.
