[PMC free article] [PubMed] [Google Scholar] 3. factors for OS were nivolumab treatment (hazard ratio [HR], 0.536; 95% confidence interval [CI], 0.300C0.957; =0.04), male sex (HR, 2.587; Beta Carotene 95% CI, 1.140C5.872; =0.02), Child-Pugh class B (HR, 5.195; 95% CI, 2.073C13.018; =0.001), and intrahepatic tumor burden (HR, 2.801; 95% CI, 1.019C7.703; =0.046). Regarding safety, patients treated with nivolumab or regorafenib had comparable toxicity leading to premature drug discontinuation, mostly from hepatic decompensation. The authors suggest that patients with Child-Pugh class B would tolerate nivolumab better than regorafenib, as there was no difference in discontinuation rates due to hepatic decompensation despite the larger number of patients with Child-Pugh class B in the nivolumab group (18.8% vs. 3.9%; =0.003). The authors applied inverse probability of treatment weighting (IPTW) to reduce treatment selection bias, which is unavoidable in retrospective studies. In fact, the baseline characteristics were not well-balanced between the two groups. In addition Beta Carotene to the difference in sample size (n=48 in nivolumab, n=102 in regorafenib), a greater proportion of patients in the nivolumab group (18.8%) had poor liver function (indicated by Child-Pugh score 7C9) compared to those in the regorafenib group (3.9%). Additionally, the proportion of patients with intrahepatic tumor burden 50% tended to be higher in the nivolumab group (27.1%) than in the regorafenib group (18.6%), although the difference was not statistically significant (=0.40). Even after IPTW, nivolumab treatment remained a significant independent factor associated with prolonged OS (HR, 0.340; 95% CI, 0.177C0.653; =0.001). However, in the multivariate analysis after IPTW, nivolumab treatment was not found to be an independent factor related to prolonged TTP (HR, 0.744; 95% CI, 0.394C1.405; =0.36). Based on the results obtained using IPTW, the authors concluded that nivolumab treatment might be associated with prolonged OS compared to regorafenib treatment in patients who progressed afterwards or were intolerant of sorafenib. Although IPTW estimation is now commonly used to control for confounding factors in nonexperimental studies of medical interventions [11], not all of the confounders could be adjusted. In the study by Lee et al [9]., the median duration of sorafenib treatment was 2.5 months (1.4C3.1) and 3.0 months (2.3C6.2) in the nivolumab and regorafenib groups, respectively (=0.238) [12]. Consequently, if similar experience is possible with nivolumab, which has been accepted as a secondline drug based on phase 1/2 data, the role of an immune checkpoint inhibitor as rescue therapy after sorafenib failure might not be so promising. At present, a possible approach to a systemic treatment strategy can be suggested in light of the available data. Patients who were tolerant of sorafenib and had disease progression would be managed with regorafenib as second-line therapy, according to RESORCE trial [5]. Cabozantinib, a multiple receptor tyrosine kinases inhibitor inhibiting VEGFR2, c-MET, and AXL, was approved as a second-line and third-line treatment for advanced HCC. In subgroup analysis, cabozantinib demonstrated favorable effects in patients aged 65 years, males, and those with extrahepatic spread [6]. Patients who discontinued sorafenib due Beta Carotene to toxicity would be considered for nivolumab, cabozantinib, or ramucirumab. Nivolumab was tested in an open-label, non-comparative, phase 1/2 dose study (Checkmate 040) that assessed the safety and efficacy of nivolumab in patients with HCC who failed sorafenib treatment or other systemic therapy and those who were intolerant to sorafenib [7]. Ramucirumab, for which survival benefit compared to placebo is not meaningful in patients who failed or were intolerant to sorafenib (8.5 vs. 7.3 months), showed improved survival in patients whose alpha-fetoprotein (AFP) concentrations are 400 ng/mL or greater [8]. Therefore, ramucirumab should be restricted to patients whose RAF1 AFP concentrations are 400 ng/mL or greater in both sorafenib intolerant and tolerant patients (Fig. 1) [8]. However, CELSTIAL trial (phase 3 double-blind placebo-controlled trial randomizing 773 HCC patients to cabozantinib or placebo in the second- or third-line setting) also reported favorable response to this particular subgroup (AFP 400 ng/mL); therefore, uncertainty remains on the superiority of ramucirumab over other treatment agents as second-line.