**5. Current treatment of NAFLD-associated HCC**

Current HCC treatment recommendations incorporate Barcelona Clinic Liver Cancer (BCLC) stage, liver lesion number and size, liver function and patient performance status [51]. Treatment modalities for localized disease include hepatic resection, ablation, and liver transplant for single or small lesions; chemoembolization and stereotactic radiation for larger, multiple unresectable lesions. These locoregional treatments seem to be equally effective regardless of HCC etiology. A comprehensive review on different locoregional treatment modalities in NAFLD-associated HCC has been published recently [52]. This chapter will focus on systemic therapies, especially immune checkpoint inhibitors in NAFLD-associated HCC.

### **5.1 Tyrosine kinase inhibitor (TKI)**

### *5.1.1 Sorafenib*

The Phase III SHARP trial established the efficacy of sorafenib, a multikinase inhibitor, which prolonged the median survival and median time to radiographic progression for patients with locally advanced or metastatic HCC [53]. A similar Phase III trial that was conducted in Asian-Pacific region observed similar results [54]. In the SHARP study, 48% patients had viral hepatitis as an etiology of HCC and the percentage of NAFLD-associated HCC is unknown. The subsequent published subgroup analysis of SHARP study patients and combined analysis of SHARP study and Asian-Pacific study patients didn't include NAFLD-associated HCC as a subgroup either [55, 56]. A recent presented study of 5201 patients with HCC treated with sorafenib found that there is no overall survival or adverse event difference between NAFLD-associated HCC and other etiology related HCC. However, patients with NAFLD-associated HCC were significantly older and sorafenib was commenced at more advanced stages. There were only 3.6% patients with NAFLD-associated HCC in the study, limiting the ability of drawing definite conclusions [57].

#### *5.1.2 Lenvatinib*

Lenvatinib, another multikinase inhibitor, showed non-inferiority to sorafenib in the Phase III REFLECT study [58]. Similar to SHARP study, patients in REFLECT study was characterized as having viral etiologic HCC or alcohol related HCC. The percentage of NALFD-associated HCC is unknown. A recently published multi-center retrospective study from Japan included 530 HCC patients treated with Lenvatinib [59]. The study compared the survival of 103 patients with NAFLD-associated HCC with that of 427 patients with HCC from other etiologies and revealed that progression free survival was statistically better in patients with NAFLD-associated HCC (9.3 vs. 7.5 months, P = 0.012), and overall survival was numerically better even though not statistically significant (20.5 vs. 16.9 months, P = 0.057).

#### *5.1.3 Other TKIs*

Regorafenib was approved as a second-line treatment for advanced HCC after progressing on sorafenib based on the Phase III RESORCE study [60]. Ramucirumab was also approved for the same indication after showing overall survival and

progression free survival benefit in patients with advanced HCC in REACH-2 study [61]. Multikinase inhibitor cabozantinib improved survival and PFS in patients who have failed one or two lines of treatment in the study CELESTIAL and cabozantinib was the first approved third-line treatment for advanced HCC [62]. In these three studies, subgroup analysis didn't show different response to these TKIs according to HCC etiology. In a retrospective study that included 23.5% NAFLD-associated HCC also showed similar responses to regorafenib regardless of HCC etiologies. However, there were less than 10% of NAFLD-associated HCC patients included in RESORCE, REACH-2 and CELESTIAL studies. And there were less than 25 patients in the retrospective study mentioned above. The small number of patients enrolled in the studies limit definitive conclusions.

#### **5.2 Immune checkpoint inhibitors**

Checkpoint inhibitor single agent was first studied in the second line settings. Both nivolumab and pembrolizumab showed improved response rate in the early phase clinical trials [63, 64]. Based on the results from these studies, FDA granted accelerated approval for advanced HCC. Pembrolizumab was further tested in the second line setting in KEYNOTE 240 study. However, the study didn't meet the primary endpoint of superior combined OS and PFS [65]. Similarly, Phase III CheckMate 459 study comparing nivolumab with sorafenib in the first line setting didn't show superiority of nivolumab [66]. Combing nivolumab and ipilimumab at different dose and schedule was explored and doublet regimen has shown improved response rate up to 30% in the second line setting [67]. Phase III HIMALAYA study added tremelimumab to durvalumab and compared this regimen with sorafenib. The combination treatment improved overall survival compared to sorafenib and the final results are eagerly anticipated [68].

As with studies of TKIs in HCC, most studies of immune checkpoint inhibitors stratified patients to groups of HBV related, HCV related and uninfected, and the percentage of NAFLD-associated HCC in the uninfected group is unknown. Nevertheless, subgroup analysis in most of these studies showed comparable efficacy of immune checkpoint inhibitors in uninfected and overall population (**Table 1**).

#### **5.3 Immune checkpoint inhibitor and VGEF inhibitor**

The combination of immune checkpoint inhibitor atezolizumab and VEGF inhibitor bevacizumab in patients with locally advanced or metastatic HCC in the first setting has shown superior OS and PFS compared to sorafenib in IMbrave150 trial [69]. The median OS was 19.2 months with atezolizumab plus bevacizumab and 13.4 months with sorafenib (hazard ratio 0.66; 95% CI 0.52–0.85; p <0.001). The median PFS was 6.9 and 4.3 months in the respective treatment groups (HR 0.65; 95% CI 0.53–0.81; p < 0.001). The combination was approved by FDA as first line treatment for HCC in 2020 and is the preferred first line treatment over single agent immune checkpoint inhibitor or TKIs in eligible patients.

The percentage of NAFLD-associated HCC is unknown in this study but 30% of the patients had no viral infection. In the subgroup analysis, uninfected patients with HCC seemed to have derived less benefit from the combination treatment compared to patients with viral hepatitis (HR for death 1.05; 95% CI 0.68–1.63) [70]. A previous animal study has demonstrated the existence of a CD8+PD-1+ subset of protumorigenic cells in NASH that favor the development of HCC and hamper response


*Non-alcoholic Fatty Liver Disease Associated Hepatocellular Carcinoma DOI: http://dx.doi.org/10.5772/intechopen.106816*

*Abbreviations: HBV: hepatitis B; HCV: hepatitis C; BSC: best supportive care; ORR: objective response rate; CR: complete remission; PR: partial remission; OS: overall survival; PFS: progression free survival.\* OS hazard ratios in patients with HBV, HCV and uninfected were 0.57 (0.35–0.94), 0.96 (0.48–1.92) and 0.88 (0.64–1.20) respectively. PFS hazard ratios in patients with HBV, HCV and uninfected were 0.70 (0.44–1.13), 0.46 (0.24–0.90), 0.75 (0.56–1.01).*

*# Arm A: nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks; Arm B: nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks; Arm C: nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (arm C).*

*^ Median overall survival of patients who were HBV/HCV uninfected, HBV infected, or HCV infected in arm A was 22.2 months, 22.8 months, and 14.9 months; in arm B, 11.8 months, 12.1 months, and 16.1 months; and in arm C, 7.4 months, 9.6 months, and 33.0 months, respectively.*

#### **Table 1.**

*Overview of outcomes of checkpoint inhibitor studies in patients with locally advanced or metastatic hepatocellular carcinoma.*

to immune checkpoint inhibitors. The authors also performed meta-analysis using data from CheckMate 459, IMbrave150 and KEYNOTE240, and revealed that patients with non-viral etiology had inferior survival when treated with immune checkpoint inhibitors. They then performed a cohort study of 130 patients with HCC from various etiologies and patients with NAFLD associated HCC had shorter overall survival of 5.4 months vs. 11 months in patients with HCC from other etiologies.

The better response to immunotherapy in patients with viral-induced HCC than in patients with NAFLD associated HCC might be due to the amount or quality of viral antigens or to a different liver micro-environment, possibly one that does not impair immune surveillance. Stratifying clinical trials according to HCC etiology for prospective validation in future clinical trials is warranted.
